Heterocyclic derivatives

ABSTRACT

Compounds of formula I ##STR1## and metabolically labile esters and amides thereof, and pharmaceutically acceptable salts thereof, in which R 13 , M 2 , X 1 , Z 1 , Z 1a , X 2  and A 1  have the meanings given in the specification. The compounds are useful as inhibitors of the binding of fibrinogen to glycoprotein IIb/IIIa. Novel intermediates are also disclosed.

This is a continuation of U.S. Ser. No. 08/457,538 filed Jun. 1, 1995,now U.S. Pat. No. 5,652,242 which is a continuation-in-part of U.S. Ser.No. 08/218,171 filed Mar. 28, 1994, now U.S. Pat. No. 5,563,141.

The present invention relates to a group of heterocyclic derivativeswhich inhibit cell adhesion (for example, platelet aggregation), toprocesses for their preparation and to pharmaceutical compositionscontaining them.

A variety of diseases involve cell adhesion during their development.For example, platelet aggregation is involved in the formation of bloodthrombi, which can lead to diseases such as thrombosis, (eg stroke andthrombotic events accompanying unstable angina and transient ischaemicattack), myocardial infarction, atherosclerosis, thromboembolism andreocclusion during and after thrombolytic therapy.

It is widely believed that the platelet membrane glycoprotein IIb/IIIa(GPIIb/IIIa) mediates platelet aggregation. Adhesion molecules such asfibrinogen and yon Willebrand Factor are believed to bind to GPIIb/IIIasites on adjacent platelets and thereby cause them to aggregate. Otheradhesion molecules which are known to bind to the GPIIb/IIIa arefibronectin, vitronectin and thrombospondin.

Surprisingly, as a result of random screening, the ability to inhibitplatelet aggregation and to inhibit the binding of fibrinogen toGPIIb/IIIa has now been found to be possessed by certain heterocyclicderivatives containing a 4- (4-pyridyl)piperazin-1-yl or related group.

According to one aspect, therefore, the present invention provides acompound of the general formula ##STR2## wherein:

M² is --NR³ -- in which R³ is hydrogen or (1-4C)alkyl; or is --NR⁴--D--TR⁵ -- in which

(i) T is N; D is CH₂ CO; CH₂ SO₂ ; (2-3C)alkylene optionally substitutedby carboxy, (1-4C)alkoxycarbonyl or (1-4C)alkoxymethyl; and R⁴ and R⁵together represent (2-3C)alkylene or CH₂ CO, or each independentlyrepresents hydrogen or (1-4C)alkyl; or

(ii) T is CH; D is CH₂ CO, CH₂ CH₂ NH, (1-3C)alkylene optionallysubstituted by carboxy or (1-4C)alkoxycarbonyl, or (2-3C)alkyleneoxy;and R⁴ and R⁵ together represent (1-3C)alkylene; or

(iii) R⁴ and --D--TR⁵ -- together form a (5-6C)alkenylene group.

X¹ is a bond or (1-4C)alkylene, (2-4C)alkenylene, (2-4C)alkynylene,(1-2C)alkylenephenylene, phenyleneoxy, phenyleneoxymethylene,phenylenecarbonyl, phenyleneCONH, (1-3C)alkylenecarbonyl,(1-2C)alkylenecarbonyl substituted by benzyl or p-hydroxybenzyl,methylidenepyrrolidin-1-ylacetyl, (1-2C)-alkylenecarbonyloxy,(1-2C)alkyleneCONH, (1-2C)alkyleneCONH(1-2C)alkyleneCO,(1-2C)alkyleneCONH(1-2C)-alkyleneCONH, benzyl(1-2C)alkyleneCONH,(1-4C)alkyleneoxy, (1-2C)alkyleneoxy(1-2C)alkylene,(1-2C)alkyleneoxy(1-2C)-alkylenecarbonyl, (1-3C)alkyleneCH(OH), and,when M² is --NR⁴ --D--TR⁵ --, carbonyl, carbonyl(1-3C)alkylene, CONH,(1-2C)alkyleneNHCO and CONH(1-3C)alkylene, and when T is CH, oxy,oxy(1-3C)alkylene, oxy(1-2C)alkylenecarbonyl oroxy(1-2C)alkylenephenylene;

or X¹ together with M² may form a group of formula: ##STR3##

Z¹ and Z^(1a) each independently represents hydrogen, hydroxy, halogeno,(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,(1-4C)alkylthio, (2-4C)alkenyloxy, nitro, amino, (1-4C)alkylamino,(2-4C)alkanoylamino, cyano, (1-4C)alkylsulphonylamino;phenyl(1-2C)sulphonylamino, p-toluenesulphonylamino, or(1-4C)alkoxycarbonyl, or has one of the meanings given for X² --A¹ ;

X² is a bond or (1-4C)alkylene, (2-4C)alkenylene, oxy(1-4C)alkylene,oxy(5-6C)alkylene, oxy(2-4C)alkenylene, thio(1-3C)alkylene, SO₂(1-3C)alkylene, amino(1-3C)alkylene, SO₂ NH(1-3C)alkylene, NR²¹CO(1-2C)alkylene (where R²¹ represents hydrogen, (1-4C)alkyl or benzyl),CONR²¹ (1-2C)alkylene, in any of which the alkylene group may optionallybe substituted by (2-4C)alkenyl; (2-4C)alkynyl; (1-4C)alkoxy; carboxy;(1-4C)alkoxycarbonyl; phenyl(1-4C)alkoxycarbonyl; phenyl(1-2C)alkylNHCO;carboxy(1-2C)alkyl; phenyl(1-2C)alkyl; phenylsulphonyl(1-2C)alkyl;pyridyl, phenyl; amino or a group of formula NR¹² XR⁶ in which X is SO₂,CO or CO₂ ; R¹² is hydrogen or (1-4C)alkyl and R⁶ is (1-6C)alkyl,(6-10C)aryl, (6-10C)aryl(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl,morpholino(1-4C)alkyl, piperidino(1-4C)alkyl orN-(1-4C)alkylpiperidino(1-4C)alkyl.

A¹ is carboxy or a metabolically labile ester or amide thereof; and

R¹³ is hydrogen, (1-4C)alkyl, (1-4C)alkoxy or halogen; andpharmaceutically acceptable salts thereof.

Without wishing to be bound by theory, it is believed that the nitrogenatom in the pyridyl group functions as a replacement for the stronglybasic guanidine group in arginine. The function of the nitrogen atomwhich is attached to pyridyl in the group represented by M² is believedto be to contribute to the ability of the nitrogen atom in the pyridylgroup to function as a base. For example a 4-(4-pyridyl)piperazin-1-ylgroup, the nitrogen atom in the piperazin-1-yl group is believed tocontribute to the ability of the nitrogen atom in the pyridyl group tofunction as a base as shown below: ##STR4##

Examples of values for --NR₃ -- when R³ is hydrogen or (1-4C)alkyl areNH and methylimino.

Examples of values for --NR⁴ --D--TR⁵ -- when T is N are5-oxoimidazolidin-1,3-diyl, 2-oxopiperazin-1,4-diyl,2,6-dioxopiperazin-1,4-diyl, 1,1-dioxo-1,2,5-thiadiazin-2,5-diyl,piperazin-1,4-diyl, 2-carboxypiperazin-1,4-diyl,3-carboxypiperazin-1,4-diyl, 2-methoxycarbonylpiperazin-1,4-diyl,3-methoxycarbonylpiperazin-1,4-diyl, 2-methoxymethylpiperazin-1,4-diyl,3-methoxymethylpiperazin-1,4-diyl andN-2-(N'-methylamino)ethyl(N-methyl)amino.

Examples of values for --NR⁴ --D--TR⁵ -- when T is CH arepyrrolidin-3,1-diyl, 3-oxo-pyrrolidin-4,1-diyl2-carboxypyrrolidin-4,1-diyl, 2-methoxycarbonylpyrrolidin-4,1-diyl,2-ethoxycarbonylpyrrolidin-4,1-diyl, piperidin-3,1-diyl,piperidin-4,1-diyl, piperazin-2,4-diyl and morpholin-2,4-diyl.

An example of a group of formula --NR⁴ --D--TR⁵ -- in which R⁴ and--D--TR⁵ -- together form a (5-6C)alkenylene group is1,2,3,6-tetrahydropyridin-4,1-diyl.

Particularly preferred values for M² are piperazin-1,4-diyl,piperidin-4,1-diyl and 2-oxo-piperazin-1,4-diyl.

Examples of values for X¹ are a bond, methylene, ethylene, propylene,1-methylethylene, ethenylene, ethynylene, methylenephenylene,phenyleneoxy, phenyleneoxymethylene, phenylenecarbonyl, phenyleneCONH,methylenecarbonyl, ethylenecarbonyl, 1-methylethylenecarboxyl,ethylidinecarbonyl, 2-propylidenecarbonyl, benzylmethylenecarbonyl,p-hydroxybenzylmethylenecarbonyl, methylidenepyrrolidin-1-ylacetyl,methylenecarbonyloxy, methyleneCONH, methyleneCONHmethyleneCONH,benzylmethyleneCONH, methyleneoxy, ethyleneoxy, propyleneoxy,butyleneoxy, methyleneoxymethylene, methyleneoxymethylenecarbonyl,methyleneCH(OH), and, when M² is --NR⁴ --D--TR⁵ --, carbonyl,carbonylmethylene, carbonylethylene, CONH, methyleneNHCO, CONHmethylene,and when T is CH; oxy, oxymethylene, methyleneNHCO, oxymethylenecarbonyland oxymethylenephenylene.

Particularly preferred values for X¹ include a bond, methylenecarbonyl,ethylenecarbonyl ethylidinecarbonyl, carbonyl, carbonylethylene,methyleneoxy, ethyleneoxy and, when M² is --NR⁴ --D--TR⁵ -- and T is CH;oxy.

Z¹ is preferably located ortho to X² ; that is to say at the 2 or 6position. Examples of phenylene groups optionally substituted by Z¹ andZ^(1a) are 1,4-phenylene, 2-methoxy-1,4-phenylene,3-methoxy-1,4-phenylene, 2,6-dichloro-1,4-phenylene,2,6-di-tert-butyl-1,4-phenylene, 2-carboxymethoxy-1,4-phenylene,2-methoxycarbonylmethoxy-1,4-phenylene,2-ethoxycarbonylmethoxy-1,4-phenylene, 3-methyl-1,4-phenylene,2-methyl-1,4-phenylene, 3-methoxycarbonylmethoxy-1,4-phenylene,2-allyl-1,4-phenylene, 2-propyl-1,4-phenylene, 2-nitro-1,4-phenylene,3-ethoxycarbonylmethoxy-1,4-phenylene, 3-carboxymethoxy-1,4,phenylene,and 2-tert-butyloxycarbonylmethyloxy-1,4-phenylene.

Examples of values for Z¹ and Z^(1a) are hydrogen, hydroxy, chloro,fluoro and bromo, methyl, ethyl, propyl, t-butyl, allyl, methoxy,methylthio, allyloxy, nitro, cyano, methoxycarbonyl, carboxymethoxy,methoxycarbonylmethoxy, ethoxycarbonylmethoxy andtert-butyloxycarbonylmethoxy.

Examples of values for X² are a bond, methylene, ethylene, ethenylene,oxymethylene, 2-oxyethylene, 3-oxypropylene, 2-oxyprop-2-ylene,4-oxybutylene, 5-oxypentylene, thiomethylene, aminomethylene,carboxamidomethylene, 2-carboxamidoethylene, 2-phenylethylidene,oxy(methoxycarbonyl)methylene, 1-(2-carboxyethyl)ethylene,1-(benzyloxycarbonyl)ethylene, and groups of formula CH₂ CH(NR¹² XR⁶)such as 1-(butylsulphonylamino)ethylene CH₂ CH(NHSO₂ CH₂ CH₂ CH₂ CH₃)!,1-(methylsulphonylamino)ethylene, 1-(benzylsulphonylamino)ethylene,1-p-toluenesulphonylamino)ethylene, 2-(butylsulphonylamino)ethylene,2-(p-toluenesulphonylamino)ethylene,3-oxy(1-(butylsulphonylamino)propylene), 2-carboxamido(2-phenyl)ethyleneand 2-carboxamidopropylene.

Examples of values for R¹³ are hydrogen, methyl, methoxy and chloro.Preferably R¹³ is hydrogen.

Two preferred sub-groups of compounds of formula I may be identified.One consists of those compounds of formula I in which X¹ represents abond. In this sub-group, X² preferably represents an oxy(2-4C)alkyleneor oxy(5-6C)alkylene group, especially an oxypropylene group, optionallysubstituted on the alkylene group as defined hereinabove. The otherconsists of those compounds of formula I in which X² representsoxymethylene. In this sub-group, X¹ preferably representsmethylenecarbonyl.

Examples of specifically preferred compounds are those of Examples 1, 2,3, 4, 25, 26, 35, 36, 152, 153, 154 and 155 herein.

Examples of metabolically labile ester derivatives of a carboxy groupare esters formed with alcohols such as (1-6C)alkanols, for examplemethanol, ethanol, propanol and isopropanol; indanol; adamantol;(1-6C)alkanoyloxy(1-4C)alkanols such as pivaloyloxymethyl; glycolamides;(S-methyl-2-oxo-1,3-dioxol-4-yl)methyl alcohol; and(1-4C)alkyloxycarbonyl(1-4)alkanols. It will be appreciated thatcompounds of formula I in which Z¹ is hydroxy may form internal esters.

Examples of metabolically labile amide derivatives of a carboxy groupinclude amides formed from ammonia and amines such as (1-4C)alkylamine,for example methylamine, di(1-4C)alkyl amines,(1-4C)alkoxy(1-4C)alkylamines such as methoxyethyl amine,phenyl(1-2C)alkylamines such as benzylamine; and amino acids such asglycine or an ester thereof.

It will be appreciated that certain of the compounds of general formulaI are in the form of enantiomers. It will be understood that theinvention includes any enantiomer which has the property of inhibitingplatelet aggregation and the binding of adhesion molecules toGPIIb/IIIa, whether present in a mixture with the other enantiomer (forexample in a racemic mixture), or substantially free of the otherenantiomer.

As used in this specification, the terms alkyl, alkylene, alkenylene oralkynylene include branched and unbranched groups. However, wherespecific terms are used, for example propyl, isopropyl or propylene,these indicate whether the group is branched or not. Diradicals, forexample 2-oxo-piperazin-1,4-diyl, are numbered assuming that formula Iis read from right to left with the group A¹ being at the right handside, as depicted in formula I hereinabove.

Hence, for example, 2-oxo-piperazin-1,4-diyl signifies the group:##STR5##

It will be appreciated that in this specification, the order of the twonumbers immediately preceding the term "diyl" in the name of a diradicalsignifies the orientation of the diradical in a compound of formula I.Thus the first number signifies the position in the diradical closest tothe group A¹.

Particular pharmaceutically acceptable salts include, for example, saltswith acids affording physiologically acceptable anions, such as saltswith mineral acids, for example a hydrogen halide (such as hydrogenchloride and hydrogen bromide), sulphuric acid or phosphoric acid, andsalts with organic acids, for example trifluoroacetic acid. Otherpharmaceutically acceptable salts include, for example salts withinorganic bases such as alkali metal and alkaline earth metal salts (forexample sodium salts), ammonium salts, and salts with organic amines andquaternary bases forming physiologically acceptable cations such assalts with methylamine, dimethylamine, trimethylamine, ethylenediamine,piperidine, morpholine, pyrrolidine, piperazine, ethanolamine,triethanolamine, N-methylglucamine, tetramethylammonium hydroxide andbenzyltrimethylammonium hydroxide.

According to another aspect, the invention provides a process forpreparing a compound of general formula I, or a metabolically labileester or amide thereof, or a pharmaceutically acceptable salt thereofwhich comprises

(A) For a compound of formula I in which M² is NR³ or --NR⁴ --D--NR⁵--reacting a compound of formula: ##STR6## or an acid addition saltthereof with a compound of formula: ##STR7## in which U¹ is a leavingatom or group.

Examples of values for U¹ include halogen, such as chlorine or bromine,and hydrocarbylsulphonyloxy, such as methanesulphonyloxy andp-toluenesulphonyloxy. When the group in X¹ to which U¹ is attached is acarbonyl group, U¹ may also represent a hydroxy group or a reactivederivative thereof. Examples of reactive derivatives of a hydroxyl groupinclude acyloxy groups such as acetyloxy, and groups formed in situ byreacting a compound of formula III in which U¹ is hydroxy with a peptidecoupling reagent. Examples of peptide coupling reagents includecarbodiimides such as 1,3-dicyclohexylcarbodiimide (DCC), preferably incombination with 1-hydroxybenzotriazole hydrate (HOBT).

Examples of acid addition salts include, for example the hydrochlorides.

The reaction may conveniently be effected at a temperature in the rangeof from -10° to 120° C., preferably from 10° to 100° C. Suitablesolvents include, for example, ethers such as tetrahydrofuran, amidessuch as dimethylformamide, nitriles such as acetonitrile, halogenatedhydrocarbons such as dichloromethane and alcohols such as ethanol orisopropanol.

In some circumstances, for example when an acid addition salt of acompound of formula II is used as starting material, or when thecompound of formula II is relatively unreactive, the reaction mayadvantageously be performed in the presence of a base. Examples ofsuitable bases include tertiary amines, such as triethylamine, andalkali metal hydroxides, carbonates and bicarbonates, such as sodium orpotassium hydroxide, carbonate or bicarbonate. When the compound offormula II is relatively unreactive a strong base such as an alkalimetal hydride, for example potassium hydride, may conveniently be used.

(B) For a compound of formula I in which A¹ is carboxy, decomposing anester of formula: ##STR8## in which R²⁰ is a carboxyl protecting group.

R²⁰ may be any conventional carboxyl protecting group that may beremoved without interfering with other parts of the molecule. Examplesof carboxyl protecting groups include (1-6C)alkyl groups (such asmethyl, ethyl, propyl or t-butyl), phenyl and benzyl, the phenyl moietyin any of which may optionally bear 1 or 2 of halogeno, (1-4C)alkyl,(1-4C)alkoxy or nitro.

The decomposition may be carried out using any one or more of theconventional reagents and conditions known in the art for convertingcarboxylic esters into carboxylic acids. Thus, for example, thedecomposition may conveniently be performed by base catalysedhydrolysis, for example by using an alkali metal hydroxide such aslithium, potassium or sodium hydroxide, or a tertiary amine such astriethylamine in the presence of water. The base catalysed hydrolysismay conveniently be performed in the presence of a solvent such as analcohol, for example methanol or ethanol, or an ether such astetrahydrofuran or dioxan. Alternatively the decomposition may becarried out by acid catalysed hydrolysis, for example using aqueousacetic acid or trifluoroacetic acid. The temperature is conveniently inthe range of from -10° to 100° C., for example from 10° to 50° C. Whenthe alcohol residue is t-butyl, this may also conveniently be removed byheating, for example at a temperature in the range of from 80° to 150°C., alone or in the presence of a suitable diluent such as diphenyletheror diphenylsulphone. A benzyl group may conveniently be removed bycatalytic hydrogenation, for example by hydrogenation in the presence ofpalladium on carbon at a temperature in the range of from -10° to 100°C. in the presence of a solvent such as an alcohol, for example methanolor ethanol.

(C) Reacting a compound of formula: ##STR9## in which U³ is a leavingatom or group, with a compound of formula: ##STR10## or an acid additionsalt thereof.

Examples of values for U³ include halogen, such as chlorine or bromine,and cyano.

Examples of acid addition salts include, for example the hydrochlorides.

The reaction may conveniently be effected at a temperature in the rangeof from -10° to 120° C., preferably from 10° to 100° C. Suitablesolvents include, for example, ethers such as tetrahydrofuran anddioxan, amides such as dimethylformamide, nitriles such as acetonitrile,halogenated hydrocarbons such as dichloromethane, alcohols such asethanol and water.

In some circumstances, for example when an acid addition salt of acompound of formula VIII is used as starting material, the reaction mayadvantageously be performed in the presence of a base. Examples ofsuitable bases include tertiary amines, such as triethylamine, andalkali metal hydroxides, carbonates and bicarbonates, such as sodium orpotassium hydroxide, carbonate or bicarbonate.

(D) For a compound of formula I in which X¹ comprises a CONH group,reacting the appropriate carboxylic acid of formula: ##STR11## in whichX^(1a) is a residue of a carboxylic acid group, or a reactive derivativethereof, with the appropriate amine of formula: ##STR12## in whichX^(1b) is a residue of an amine group.

Examples of values for X^(1a) are (1-2C)alkyleneCOOH,benzyl(1-2C)alkyleneCOOH and COOH. Examples of values for X^(1b) are H₂N and H₂ N(1-3C)alkylene.

Examples of reactive derivatives of the compounds of formula IX includeacyl halides such as the chlorides and bromides and groups formed insitu by reacting a residue of a carboxylic acid with a peptide couplingreagent, such as a carbodimide, for example1,3-dicyclohexylcarbodiimide, preferably in combination with1-hydroxybenzotriazole hydrate (HOBT).

The reaction is conveniently performed at a temperature in the range offrom 0° to 100° C. Suitable solvents include halogenated hydrocarbonssuch as dichloromethane, amides such as dimethylformamide and tertiaryamines such as triethylamine.

(E) For a compound of formula I in which X¹ is (2-4C)alkenylene,reacting a compound of formula: ##STR13## in which X^(1c) is anappropriate aldehyde-containing group with the appropriate Wittigreagent of formula: ##STR14## in which X^(1d) is atriarylphosphonylalkylene group such as triphenylphisphonylmethylene.

The reaction is conveniently performed at a temperature in the range offrom -20° to 50° C., preferably from 0° to 25° C. Convenient solventsinclude ethers such as tetrahydrofuran, sulphoxides such asdimethylsulphoxide and aromatic hydrocarbons such as toluene.

(F) For a compound of formula I in which X¹ comprises an oxy (ether)link, reacting the appropriate compound of formula: ##STR15## with theappropriate compound of formula: ##STR16## in which one of X^(1e) andX^(1f) is a residue of an alcohol group, and the other is a residue ofan alcohol group or a group containing a leaving atom or group.

When X^(1e) and X^(1f) both represent residues of alcohol groups, thereaction may conveniently be effected in the presence of a dehydratingagent such as diethyl azodicarboxylate-triphenylphosphine. Suitablesolvents for the reaction include ethers such as tetrahydrofuran andamides such as dimethylformamide. The reaction is conveniently effectedat a temperature in the range of from 0° to 50° C.

(G) For a compound of formula I in which X² is CH₂ CN(NHXR⁶) reacting acompound of formula: ##STR17## in which X^(2a) is CH₂ CH(NH₂), or anacid addition salt thereof, with a compound of formula

    R.sup.6.X.U.sup.4                                          XVI

in which U⁴ is a leaving atom or group.

Examples of values for U⁴ include halogen, such as chlorine or bromine.Examples of acid addition salt include for example, the hydrochloride.The reaction may conveniently be effected at a temperature in the rangeof from -10° to 120° C. preferably from 10° to 100° C. Suitable solventsinclude for example ethers such as tetrahydrofuran, amides such asdimethylformamide, nitriles such as acetonitrile, halogenatedhydrocarbon such as dichloromethane and alcohols such as ethanol. Thereaction is conveniently performed in the presence of a base, forexample a tertiary amine such as triethylamine.

(H) For a compound of formula I in which X² represents oxyalkylene oroxyalkenylene, reacting a compound of formula ##STR18## with theappropriate compound of formula

    X.sup.2d --A.sup.1                                         XIX

in which X^(2c) is a hydroxy group, or a reactive derivative thereof(such as a halide), and X^(2d) is a hydroxyalkylene or hydroxyalkenylenegroup, or a reactive derivative thereof (such as a halide, for example abromide).

The reaction is conveniently performed in the presence of a strong base,such as an alkali metal hydride, for example, sodium hydride. Suitablesolvents include amides, such as dimethylformamide. The reaction isconveniently performed at a temperature in the range of from 0° to 100°C.

(I) For a compound of formula I in which X² represents CONHalkylene,reacting a compound of formula ##STR19## with the appropriate compoundof formula

    X.sup.2f --A.sup.1                                         XXI

in which X^(2e) represents a carboxyl group or a reactive derivativethereof (such as an acyl halide, for example an acyl chloride, oranhydride) and X^(2f) represents an aminoalkylene group, or an acidaddition salt thereof (such as a hydrochloride).

Suitable solvents include halogenated hydrocarbons such asdichloromethane, amides such as dimethylformamide and tertiary amines,such as triethylamine. The reaction is conveniently performed at atemperature in the range of from 0° to 100° C.

(J) For a compound of formula I in which X¹ represents CONH orCONHalkylene, reacting a compound of formula II with a compound offormula ##STR20## in which X^(1g) is a bond or an alkylene group.

The reaction is conveniently performed at a temperature in the range offrom 0° to 100° C. Suitable solvents include halogenated hydrocarbons,such as dichloromethane.

(K) For a compound of formula I in which X¹ is(1-2C)alkylenecarbonyloxy, reacting a compound of formula ##STR21## inwhich X^(1k) represents (1-2C)alkylenecarboxy or a reactive derivativethereof, with a compound of formula ##STR22##

The reaction is conveniently performed at a temperature in the range offrom 0° to 100° C. Suitable solvents include halogenated hydrocarbonssuch as dichloromethane.

(L) For a compound of formula I in which X¹ represents(1-3C)alkylenecarbonyl, reacting a compound of formula ##STR23## inwhich X¹¹ represents a (1-3C)alkylenecarboxyl group, or a reactivederivative thereof, with a compound of formula VI in the presence of aLewis acid.

Example of suitable Lewis acids include aluminium trichloride. Examplesof reactive derivatives of compounds of formula XXVIII include thehalides, such as the chlorides.

The reaction is conveniently performed at a temperature in the range offrom -10° to 50° C. Suitable solvents include halogenated hydrocarbons,such as dichloromethane.

(M) For a compound of formula I in which X² represents NR²¹CO(1-2C)alkylene, reacting a compound of formula ##STR24## with acompound of formula

    X.sup.2h --A                                               XXX

in which X^(2h) represents a carboxy(1-2C)alkyl group, or a reactivederivative thereof.

Examples of reactive derivatives of compounds of formula XXX includehalides, such as chlorides, and anhydrides.

The reaction is conveniently performed at a temperature in the range offrom 0° to 100° C. Suitable solvents include amides such asdimethylformamide.

Certain compounds of formula I may be converted into other compounds offormula I using conventional methods. For example, a compound of formulaI in which X¹ is a (2-4C)alkylene group may be prepared by hydrogenatinga corresponding compound of formula I in which X¹ represents a(2-4C)alkenylene group. The hydrogenation may be effected, for example,in the presence of palladium on charcoal and in a suitable solvent suchas an alcohol, for example ethanol. A compound of formula I in which X¹is (1-3C)alkyleneCH(OH) may be prepared by reducing a correspondingcompound of formula I in which X¹ is (1-3C)alkylenecarbonyl. Thereduction may be effected, for example, using an alkali metalborohydride such as sodium borohydride.

The intermediates used in the aforementioned processes are known or maybe prepared by methods analogous to those known for the preparation ofknown compounds.

Thus, the compounds of formula IV may be prepared by methods analogousto processes (A) and (C) to (G) herein, but starting from theappropriately protected starting materials. It will be appreciated thatsome compounds of formula IV are compounds according to the invention.

The compounds of formula II in which M² is a 2-oxopiperazin-1,4-diylgroup may be prepared by reacting piperazinone with a compound offormula VII.

The compounds of formula XV may be prepared by deprotecting acorresponding compound of formula: ##STR25## wherein X^(2b) is CH₂CH(NHR¹¹) and R¹¹ is an amine protecting group.

Examples of amine protecting groups include oxycarbonyl groups such asbenzyloxycarbonyl. A benzyloxycarbonyl group may conveniently beremoved, for example, by hydrogenation in the presence of a palladiumcarbonyl such as palladium on charcoal.

The compounds of formula XVII may be prepared by a method analogous tothe preparation of a compound of formula I, but starting from theappropriate starting material. For example, if a compound of formulaXVII in which X¹ is methyleneoxy is desired, this may be prepared by amethod analogous to process (F) herein, starting with a compound offormula XIII and the appropriate N-protected derivative of tyrosine.

The compounds of formula XVIII may be prepared by reacting a compound offormula VII with a compound of formula ##STR26## in which X^(2g) is ahydroxy group or a protected derivative thereof (for example a methoxygroup), followed if necessary by the removal of any protecting group,(for example by treatment with hydrobromic acid) and, if desired,conversion of the hydroxy group into a reactive derivative thereof by aknown method.

Many of the intermediates, for example compounds of formulae XV, XVIIand XVIII, and the compounds of formula II and VIII in which M² is2-oxopiperazin-1,4-diyl are novel and form further aspects of thisinvention.

The compounds of formula I may be converted into pharmaceuticallyacceptable salts and/or metabolically labile esters or amides thereof bymethods well known in the art. For example, a pharmaceuticallyacceptable salt may be formed by reacting a compound of formula I withan acid capable of affording a physiologically acceptable anion, or abase capable of affording a physiologically acceptable cation. Apharmaceutically acceptable metabolically labile ester or amide may beformed respectively by esterifying a compound of formula I using aconventional technique, or reacting an acid, or a reactive derivativethereof with the appropriate amine.

The ability of the compounds of formula I to inhibit plateletaggregation may be demonstrated using a standard test (a) based on thatdescribed by Born (Nature, 1962, 194, 927-929) and involving:

(i) aggregating human, citrated, platelet-rich plasma by addition ofadenosine diphosphate so as to generate a dose-response curve;

(ii) generating a dose-response curve for ADP stimulated plateletaggregation in the presence of increasing amounts of a test compound(generally in the range 10⁻⁵ M to 10⁻¹⁰ M); and

(iii) calculating a pA₂ value indicating potency of platelet aggregationinhibition for the test compound, averaged over several concentrations,from the calculated 50% response value for ADP aggregation in thepresence and absence of the test compound.

Test (a) may be modified so as to assess the effects of a test compoundex vivo on the aggregation of human blood platelets after administrationof the test compound to a laboratory animal, such as a rat, rabbit,guinea pig, mouse or dog. For example, groups of four male, fastedAlderley Park Wistar rats are orally dosed with a test compound orappropriate vehicle, and at suitable time intervals (1,3,5 and 8 hoursafter dosing) animals are anaesthetised with fluothane and bled by heartpuncture. Blood is collected into 3.2% citrate (1 part to 9 parts wholeblood) and platelet poor plasma (ppp) prepared by centrifugation (4500×gfor 10 min).

Human blood is collected into 3.2% trisodium citrate (1 part to 9 partswhole blood) and centrifugated (200×g for 15 min) to produce plateletrich plasma (prp).

Equal volumes (125 μl) of rat ppp and human prp are mixed together, ADPadded, and the whole incubated (37° C.) and stirred (900 rpm) in aBioData platelet aggregometer. Aggregation is induced with ADP andagonist EC₅₀ values calculated for human prp/rat ppp mixtures fromanimals dosed with test compound or vehicle. A mean concentration ratio(concentration of ADP required to cause a 50% aggregation response inhuman prp/rat ppp mixtures from animals dosed with antagonist, dividedby the concentration of ADP to cause 50% aggregation in human prp/ratppp mixtures from animals dosed with vehicle) is calculated at each timepoint.

The ability of the compounds of formula I to inhibit binding offibrinogen to GPIIb-IIIa may be demonstrated using the followingstandard test (b) involving:

(i) Preparation of human platelet lysates.

Platelet rich plasma (PRP) is harvested by centrifugation (1000 rpm, 15mins) of whole blood anticoagulated with acid citrate dextrose(trisodium citrate 85 mM, citric acid 70 mM, d-glucose 110 mM) 1 part to6 parts blood. Prostacyclin (PGI₂, 1 μM) is added to the PRP beforecentrifugation (2400 rpm, 15 mins) and the resulting pellet isresuspended in modified Tyrodes' solution (NaCl 130 mM, KCl 26 mM,NaHCO₃ 12 mM, NaH₂ PO₄ 0.5 mM, MgCl₂ 1 mM, CaCl₂ 20 mM, Glucose 12 mM,HEPES 5 mM) containing bovine serum albumin 3.5 g/L, PGI₂ 1 μM andhirudin 0.5U/ml. The platelet suspension is centrifuged (2400 rpm, 15mins) and the resultant pellet resuspended in 500 μl of lysis buffer(octyl glucoside 50 mM, HEPES 10 mM, NaCl 150 mM, CaCl₂ 1 mM, MgCl₂ 1mM, PMSF 1 mM, NEM 10 mM, leupeptin 0.1 mM), agitated at 4° C. for 15minutes then centrifuged at 24000 rpm, 15 mins. The supernatant isstored at 4° C. and the pellet re-suspended in 500 μl of lysis buffer.The centrifugation process is repeated a further 3 times, the pooledsupernatants being stored at -70° C.

(ii) Receptor purification.

Glycoprotein IIb/IlIa is isolated from human platelet lysates using a mlpeptide (KYGRGDS) coupled CNBr activated Sepharose affinity column. A1.5 ml volume of platelet lysate is placed on the column and allowed tostand overnight at 4° C. Buffer (30 mls, octyl glucoside 25 mM, HEPES 10mM, NaCl 150 mM, CaCl2 1 mM, MgCl2 1 mM, PMSF 1 mM, NEM 10 mM, leupeptin0.1 mM) is passed through the column and 2 ml fractions are collectedthroughout. GPIIb/IIIa is eluted with 12 mls of buffer containingHHLGGAKQAGDV (2 mg/ml, pH 7.5), the column is washed using 4 mls bufferand the remaining GPIIb/IIIa eluted using 12 mls buffer containingGRGDSPG (1mg/ml pH 7.5). The column is finally washed using 20 mls ofbuffer and can be used for up to three such preparations. Fractionscontaining GPIIb/IIIa are identified using gel electrophoresis andimmunoblotting, pooled and stored at -70° C.

(iii) GPIIb/IIIa ELISA

96 well microtitre plates are coated with 100 μl purified human plateletfibrinogen receptor (GPIIb/IIIa) diluted in coating buffer (Tris-HCl 20mM, NaCl 150 mM, CaCl₂ 1 mM, pH 7.4) and left overnight at 4° C. Theplates are washed using washing buffer (Tris-HCl 50 mM, NaCl 100 mM,CaCl₂ 2 mM, pH 7.4) and non-specific binding blocked by the addition of200 μl 2% BSA (2 hours, 30° C.). The plates are washed prior toincubation (2 hours, 30° C.) with 100 μl biotinylated fibrinogen (10nm)containing either vehicle or test compound. The plates are washed,incubated with streptavidin (5μg/ml, 1 hour, ambient temperature), thenwashed again before the addition of 100 μl biotinylated horse radishperoxidase (0.1 μ/ml, 1 hour, ambient temperature). The plates are thenwashed and equal volumes of peroxidase substrate (3, 5, tetramethylbenzidine 0.4 g/l) and H₂ O₂ (0.02%) are mixed together immediatelybefore addition of 150 μl to each well. Colour is allowed to develop for10-15 mins before optical densities are read at 650 nM.

    ______________________________________                                        Abbreviations                                                                 ______________________________________                                        PMSF            Phenylmethylsulphonylfluoride                                 HEPES           (N- 2-Hydroxyethyl!piperazine-                                                N- 2-ethanesulphonic acid!                                    NEM             N-ethyl maleimide                                             ______________________________________                                    

The concentration of compound required to cause 50% inhibition ofbiotinylated fibrinogen binding is calculated and expressed as a pIC₅₀(-log(IC₅₀)).

In general, test compounds showing activity in this test show a pIC₅₀ ofgreater than about 4.0.

The effects of each of the compounds of formula I exemplified herein inthe above tests are given in the table below. Where a range of values isgiven, the compound has been tested more than once. A dash (-) signifiesthat a compound has not been tested.

    ______________________________________                                        TABLE OF BIOLOGICAL TEST RESULTS                                              Example                                                                              Test (a)  Test (b)                                                                              Example  Test (a)                                                                            Test (b)                              ______________________________________                                        1      6.5-6.8   5.8-6.4 34       5     4.8                                   2      7.1-7.3   7.6     35       7.5   6.7                                   3      6.3       6.6     36       7.9-8.6                                                                             8.1                                   4      8.9       9.1     37       6.9   6.5                                   5      6.0       6.0     38       7.5   7.7                                   6      7.2       7.6     39       5.7   6.6                                   7      6.3       5.2-5.4 40       8.6   8.5                                   8      6.5       7.1     41       6.5   7.9                                   9      4.9       4.3     42       5.1   6.3                                   10     5.7       6.0     43       6.8   6.6                                   11     5.7       4.4     44       7.9   8.5                                   12     6.3       7.2     45       4.8   6.7                                   13     5.3       4.4-4.8 46       6.3   7.9                                   14     5.1       <4      47       4.4   5.7                                   15     5.6       5.9     48       7.2   7.7                                   16     6.8       6.7     49       5.8   6.6                                   17     7.4       7.7     50       5.4   6.7                                   18     6.3       6.5     51       5.6   7.2                                   19     6.4       6.9     52       9     8.6                                   20     8.7       8.7     53       7.4   8.7                                   21     6.4       7.2     54       8     8.5                                   22     8.7       9.0     55       6.8   6.7                                   23     5.6       6.7     56       5.7   7.1                                   24     7.5       8.7     57       7.9   8.5                                   25     6.0-6.1   <4      58       6.5   8.6                                   26       7-7.9   7.6-8.4 59       5     5.1                                   27     5         <4      60       7.1   8.4                                   28     5.8       5.9     61       5.4   5.5                                   29     4.8       <4      62       7.6   8.5                                   30     5.5       4.8     63       5.4   6.6                                   31     7.6       7.6     64       4.4   5.4                                   32     5.5       4.4     65       6.3   7.5                                   33     7.2       7.5     66       5.7   5.6                                   67     6.7       6.4     101      6.1   7.8                                   68     5.4       4.3     102      4.9   4.3                                   69     5.9       5.4     103      4.7   6.2                                   70     6.2       5.4     104      6.4   6.6                                   71     6.0       7.0     105      8.4   7.2-7.4                               72     6.8       7.8     106      5.9   4.7                                   73     5.8       6.7     107      5.8   6.5                                   74     6.8       6.3     108      6.6   6.7                                   75     7.9       6.5     109      6.1   6.4                                   76     <4        5.4     110      4.4   5.0                                   77     4.6       4.5     111      5.2   4.3                                   78     4.2       4.5     112      5.9   6.7                                   79     4.5       <4      113      6.4-6.8                                                                             8.0-8.3                               80     6.9       5.6     114      5.9   6.2                                   81     7.2       5.5     115      6.7   8.0                                   82     5         4.9     116      5.8   4.1                                   83     6.6       5.4     117      5.5   6.0                                   84     5.8       6.3     118      4.8   5.4                                   85     5.3       5.3     119      5.5   --                                    86     5.0       4.5     120      6.5   --                                    87     5.3       5.3     121      4.8   --                                    88     5.5       5.3     122      6.0   --                                    89     5.1       5.2     123      5.9   6.5                                   90     6.4       6.2     124      4.2   4.7                                   91     7.3       7.5     125      <4    5.4                                   92     4.7       4.7     126      <4    6.6                                   93     6.5       6.5     127      4.4   6.6                                   94     6.2       5.4     128      6.3   --                                    95     7.0       7.0     129      7.9   8.4                                   96     5.5       <4      130      4.3   <4                                    97     4.7       5.8     131      --    --                                    98     6.5       7.1     132      7.2   8                                     99     6.2       7.0     133      7.1   8.9                                   100    6.3       5.7     134      6.6   --                                    135    6.6       8.0                                                          136    6.5       6                                                            137    6.5       --                                                           138    6.7       --                                                           139    6.5       --                                                           140    5.8       6.8                                                          141    7.1       --                                                           142    6.7       6.3                                                          143    --        --                                                           144    6.9       --                                                           145    5.7       --                                                           146    6.5       --                                                           147    6.0       --                                                           148    7.5       --                                                           149    5.5       --                                                           150    6.8       --                                                           151    6.1       --                                                           152    7.6       --                                                           153    8.2       --                                                           154    6.5       --                                                           155    8.0       --                                                           156    --        --                                                           ______________________________________                                    

In general, it has been found that compounds of formula I in which A¹ iscarboxy show a higher level of activity in test (a), and test (b) thanthose in which A¹ is an ester group. However, the compounds in which A¹is an ester group have often been found to show a higher level ofactivity than those where A¹ is carboxy in test (a) when the test ismodified to assess the activity of test compounds on oral administration

For example, the compound described in Example 1 hereinafter has beenfound to give a pA₂ of 6.5-6.8 in test (a) and a pIC₅₀ of 5.8-6.4 intest (b), whereas the compound of Example 2 has been found to give a pA₂of 7.1-7.3 in test (a) and a pIC₅₀ of 7.6 in test (b). However, thecompound of Example 1 has been found to be active for up to 12 hourswhen dosed orally to dogs at 5 mg/kg. Without wishing to be bound bytheory it is accordingly believed that the compounds of formula I inwhich A¹ represents an ester group function as a pro-drugs for compoundsof formula I in which A is a carboxyl group.

As stated previously, the compounds of formula I may be used in thetherapy or prevention of diseases in which cell adhesion (especiallyplatelet aggregation) is involved, for example venous or arterialthrombosis (e.g. pulmonary embolism, stroke and thrombotic eventsaccompanying unstable angina and transient ischaemic attack), myocardialinfarction, atherosclerosis, thromboembolism and reocclusion during andafter thrombolytic therapy. The compounds may also be useful for theprevention of reocclusion and restenosis following percutaneoustransluminal coronary angioplasty (PTCA) and coronary artery bypassgraft. It will also be appreciated that the compounds may be useful inthe treatment of other diseases mediated by binding of adhesionmolecules to GPIIb/IIIa, for example cancer.

According to another aspect, therefore, the invention provides a methodof inhibiting platelet aggregation in a warm-blooded mammal requiringsuch treatment, which comprises administering an effective amount of acompound of formula I, or a metabolically labile ester or amide thereof,or a pharmaceutically acceptable salt.

According to yet another aspect, the invention provides a method ofinhibiting binding of fibrinogen to GPIIb/IIIa in a warm-blooded animalrequiring such treatment, which comprises administering an effectiveamount of a compound of formula I, or a metabolically labile ester oramide thereof, a pharmaceutically acceptable salt thereof.

According to a further aspect, the invention provides the use of acompound of formula I, or a metabolically labile ester or amide thereofor a pharmaceutically acceptable salt thereof for the manufacture of amedicament for the prevention or treatment of a disease involvingplatelet aggregation.

According to yet another aspect, the invention provides the use of acompound of formula I or a metabolically labile ester or amide thereofor a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the prevention or treatment of a disease involvingbinding of fibrinogen to GPIIb/IIIa.

In general, a compound of formula I will be administered for thispurpose by an oral, rectal, topical, intravenous, subcutaneous,intramuscular or inhalation route, so that a dose in the range of from0.01 to 50 mg/kg body weight will be given, depending upon the route ofadministration, the age and sex of the patient, and the severity of thecondition to be treated.

The compounds of formula I will generally be used in the form of apharmaceutical composition comprising a compound of formula I or apharmaceutically acceptable salt thereof as defined hereinabove,together with a pharmaceutically acceptable diluent or carrier. Such acomposition is provided as a further feature of the invention and may bein a variety of dosage forms. For example, it may be in the form oftablets, capsules, solutions or suspensions for oral administration; inthe form of cream or ointments or a transdermal (skin) patch for topicaladministration; in the form of a suppository for rectal administration;in the form of a sterile solution or suspension for administration byintravenous or intramuscular injection; in the form of an aerosol or anebuliser solution or suspension, for administration by inhalation; andin the form of a powder, together with pharmaceutically acceptable inertsolid diluents such as lactose, for administration by insufflation.Depending upon the route of administration, the composition maycomprise, for example, for 0.1 to 99.9% by weight of a compound offormula I.

The pharmaceutical compositions may be obtained by conventionalprocedures using pharmaceutically acceptable diluents and carriers wellknown in the art. Tablets and capsules for oral administration mayconveniently be formed with an enteric coating, for example comprisingcellulose acetate phthalate, to minimise contact of the activeingredient of formula I with stomach acids.

The compounds according to the invention may be co-adminstrated orco-formulated with one or more agents known to be of value in diseasesor conditions intended to be treated; for example a known plateletaggregation inhibitor (e.g. aspirin, a thromboxane antagonist or athromboxane synthase inhibitor), hypolipidemic agent, anti-hypertensiveagent, thrombolytic agent (such as streptokinase, urokinase,prourokinase, tissue plasminogen activator and derivatives thereof),beta-adrenergic blocker or a vasodilator may usefully also be present ina pharmaceutical composition of the invention for use in treating aheart or vascular disease or condition.

In addition to their use in therapeutic medicine, the compounds offormula I are also useful as pharmacological tools in the developmentand standardisation of test systems for the evaluation of the effects ofadhesion molecules in laboratory animals such as cats, dogs, rabbits,monkeys, rats and mice, as part of the search for new therapeuticagents. The compounds of formula I may also be used because of theirplatelet aggregation inhibitory properties in helping to store blood andto maintain the viability of blood and blood vessels in warm-bloodedanimals (or parts thereof) under-going artificial extracorporealcirculation, for example during limb or organ transplants. When used forthis purpose a compound of formula I, or a physiologically acceptablesalt thereof, will generally be administered so that a steady stateconcentration in the range, for example, 0.1 to 10 mg. per litre isachieved in the blood.

The invention will now be illustrated by the following non-limitingExamples in which unless otherwise stated:

(i) concentrations and evaporations were carried out by rotaryevaporation in vacuo;

(ii) operations were carried out at ambient temperature, that is in therange 18°-26° C.;

(iii) column chromatography was carried out on silica (Merck Art. 9385)available from E Merck and Co., Darmstadt, Germany; and on neutralalumina (ICN Alumina N, Akt. III or IV) available from ICN BiomedicalsGmbH, D-3440 Eschwege, Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable by diligent process development;

(v) proton NMR spectra were normally determined at 200 MHz or 250 MHz indimethylsulphoxide-d₆ using tetramethylsilane (TMS) as an internalstandard, and are expressed as chemical shifts (delta values) in partsper million relative to TMS using conventional abbreviations fordesignation of major peaks: s, singlet; m, multiplet; t, triplet; br,broad; d,doublet; and

(vi) ether refers to diethyl ether, THF to tetrahydrofuran, DMF toN,N-dimethylformamide, DMSO to dimethylsulphoxide, TFA totrifluoroacetic acid; HOBT to 1-hydroxybenzotriazole; and NBA tom-nitrobenzylalcohol.

(vii) Drying with PS paper refers to the use of Whatmans PS phaseseparating paper.

EXAMPLE 1 Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenoxyacetate.

A solution of methyl 4-bromoacetylphenoxyacetate (4.3 g) in acetonitrile(50 ml) was added dropwise over 40 minutes to a stirred solution of1-(4-pyridyl)piperazine (4.9 g) in acetonitrile (100 ml). Stirring wascontinued for a further 1.5 hours, then the solution was filtered andthe filtrate evaporated in vacuo. The solid residue was triturated withwater (50 ml), then dried and suspended in methylene chloride (50 ml).The suspension was then filtered and the filtrate concentrated to asmall volume. Purification by flash chromatography on neutral aluminaeluting first with dichloromethane, then 0.5% v/vmethanol/dichloromethane and finally 1% v/v methanol/dichloromethanegave the title compound, 1.93 g, as a solid: m.p. 150°-152° C.; NMR(d⁶DMSO) δ 8.14(2H,d), 7.98(2H,d), 7.03(2H,d), 6.78(2H,d), 4.90(2H,s),3.83(2H,s), 3.72(3H,s), 3.34(4H,bt), 2.65(4H,bt); m/e 370 (M+H)⁺ ;calculated for C₂₀ H₂₃ N₃ O₄ : C, 65.0; H, 6.3; N, 11.4 found: C 65.2;H, 6.4; N,

EXAMPLE 2 4- 2- 4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxyacetic acid

A stirred solution of the product of Example 1 (550 mg) in methanol (10ml) was treated with a M sodium hydroxide solution (1.65 ml) andstirring continued for a further 2 hours. The mixture was diluted withwater (10 ml) and the resulting solution concentrated in vacuo. Water(20 ml) was added and then a M hydrochloric acid solution (1.65 ml). Oncooling to 4° C., a solid precipitated. This mixture was concentrated invacuo, the solid collected and washed with ice-water, then dried to givethe title compound, 320 mg, as a solid: m.p. 294°-296° C; NMR (d⁶DMSO+TFA) δ 8.34(2H,d), 7.95(2H,d), 7.26(2H,d), 7.10(2H,d), 5.06(2H,s),4.82(2H,s), 4.06(4H,bs), 3.52(4H,bs); m/e 356(M+H)⁺ ; calculated for C₁₉H₂₁ N₃ O₄ : C, 64.2; H, 6.0; N, 11.8. found: C, 64.1; H, 6.1; N, 11.6%.

EXAMPLE 3 Dimethyl 2,2'- 4- 2-4-(4-pyridyl)piperazin-1-yl)-acetyl!phenylene-1,2-dioxy!diacetate.

A solution of dimethyl 2,2'- 4-bromoacetyl!phenylene-1,2-dioxy)diacetate(3.0 g) in acetonitrile (15 ml) was added dropwise over 30 minutes to astirred solution of 1-(4-pyridyl)piperazine (2.6 g) in acetonitrile (75ml) and the mixture stirred overnight. The mixture was then filtered andthe filtrate evaporated to give an oil. Purification by flashchromatography on silica eluting first with 2.5% v/vmethanol/dichloromethane then 5% v/v methanol/dichloromethane gave asolid. Trituration with ether gave the title compound, 0.95 g, as asolid: m.p. 81°-83° C.; NMR (d⁶ DMSO) δ 8.14(2H,d), 7.67(1H,dd),7.52(1H,d), 7.03(1H,d), 6.80(2H,d), 4.94(2H,s), 4.88(2H,s), 3.81(2H,s),3.69(6H,s), 3.29(4H,t), 2.60(4H,t); m/e 458 (M+H)⁺ ; calculated for C₂₃H₂₇ O₇ N₃. 0.25H₂ O: C, 59.8; H, 6.0; N, 9.1. found C, 59.7; H, 6.2; N,8.8%.

The starting material was prepared as follows:

(i) Methyl bromoacetate (19.1 ml) was added dropwise to a stirredmixture of 3,4-dihydroxyacetophenone (12.6 g) and anhydrous potassiumcarbonate (27.5 g) in acetone (250 ml). Stirring was continued for 16hours when the mixture was filtered and the solvent removed in vacuo.The residue after trituration with ether gave dimethyl 2,2'-(4-acetyl!phenylene-1,2-dioxy)diacetate, 13.1 g, as an off-white solid:m.p. 101°-102° C.; NMR (d⁶ DMSO) δ 7.60(1H,dd), 7.41(1H,d), 7.02(1H,d),4.94(2H,s), 4.89(2H,s), 3.71(6H,s), 2.50(3H,s); m/e 297(M+H)⁺ ;calculated for C₁₄ H₁₆ O₇ : C, 56.8; H, 5.4. found: C, 56.4; H, 5.5%.

(ii) A solution of bromine (2.27 ml) in chloroform (10 ml) was addeddropwise over 15 minutes to a stirred solution of the product of step(i) (12.9 g) in chloroform (40 ml) at 30° C. The mixture was thenstirred for 2 hours at ambient temperature when the solvent was removedin vacuo. The resulting waxy solid, on trituration with ethanol, gavedimethyl 2,2'-( 4-bromoacetyl!phenylene-1,2-dioxy)diacetate, 11.5 g, asa cream solid: m.p. 76°-78° C.; NMR(d⁶ DMSO) δ 7.66(1H,dd), 7.47(1H,d),7.06(1H,d), 4.96(2H,s), 4.90(2H,s), 4.62(2H,s), 3.71(6H,s); m/e 375/377(M+H)⁺, 1 Br pattern.

EXAMPLE 4 2,2'- 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenylene-1,2-dioxy!diacetic acid.

A stirred solution of the product of Example 3 (300 mg) in methanol (4ml) was treated with a M sodium hydroxide solution (1.31 ml) and themixture stirred for 1 hour. The mixture was diluted with water (10 ml)and the resulting solution concentrated to about 7 ml when a Mhydrochloric acid solution (1.31 ml) was added. On cooling to 4° C. thesolid formed was collected, then washed with ice-water and dried to givethe title compound, 120 mg, as a white solid: m.p. 180°-184° C. (dec);NMR(d⁶ DMSO) δ 8.16(2H,d), 7.61(2H,t), 6.93(1H,d), 6.87(2H,d),4.73(2H,s), 4.68(2H,s), 3.77(2H,s), 3.44(4H,bt), 2.58(4H,bt); m/e 430(M+H)⁺ ; calculated for C₂₁ H₂₃ O₇ N₃. 0.75H₂ O: C, 56.9; H, 5.5; N,9.5. found C, 57.0; H, 5.6; N, 9.3%.

EXAMPLE 5 Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-2-methoxyphenoxyacetate

A solution of methyl 4-bromoacetyl 2-methoxyphenoxyacetate (1.27 g) inacetonitrile (10 ml) was added dropwise over 15 minutes to a stirredsolution of 1-(4-pyridyl)piperazine (1.30 g) in acetonitrile (30 ml).After stirring overnight the liquors were decanted from the solidresidue, then concentrated in vacuo. Purification by flashchromatography on silica, eluting with dichloromethane then 5% v/vmethanol/dichloromethane gave a solid. Trituration with ether gave thetitle compound, 420 mg: m.p. 110°-112° C.; NMR (d⁶ DMSO) δ8,14(2H,d),7.65(1H,dd), 7.55(1H,d), 6.97(1H,d), 6.80(2H,d), 4.90(2H,s), 3.87(5H,s),3.72(3H,s), 3.33(4H,t), 2.62(4H,t); m/e 400(M+H)⁺ ; calculated for C₂₁H₂₅ N₃ O₅ : C, 63.1; H, 6.3; N, 10.5. found: C, 62.9; H, 6.3; N, 10.4%.

EXAMPLE 6 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-2-methoxyphenoxyacetic acid

In a similar manner to Example 2, but starting from the product ofExample 5, the title compound was prepared in 47% yield: m.p. 218°-224°C.; NMR(d⁶ DMSO) δ 8.16(2H,d), 7.65(1H,dd), 7.53(1H,d), 6.92(1H,d),6.85(2H,d), 4.73(2H,s), 3.86(2H,s), 3.82(3H,s), 3.36(4H,t), 2.63(4H,t);m/e 386(M+H)⁺ ; calculated for C₂₀ H₂₃ N₃ O₅. H₂ O: C, 59.5; H, 6.2; N,10.4. found: C, 59.5; H, 5.9; N, 10.1%.

EXAMPLE 7 Methyl 4- 3-4-(4-pyridyl)piperazin-1-yl!propanoyl!-phenoxyacetate

In a similar manner to Example 3, but starting from methyl 4-3-chloropropanoyl!phenoxyacetate was prepared the title compound in 65%yield: m.p. 93°-95° C.; NMR (d⁶ DMSO)δ 8.14(2H,d), 7.96(2H,d),7.04(2H,d), 6.81(2H,d), 4.92(2H,s), 3.71(3H,s), 3.29(4H,t), 3.17(2H,t),2.72(2H,t), 2.51(4H,t); m/e 384 (M+H)⁺ ; calculated for C₂₁ H₂₅ N₃ O₄ C,65.8; H, 6.6; N, 11.0. found C, 65.6; H, 6.8; N, 10.8%.

The necessary starting material was prepared as follows:

Aluminium chloride (33.35 g) was added portionwise to a stirred cooled(<0° C.) solution of methyl phenoxyacetate (14.46 ml) and3-chloropropionyl chloride (9.55 ml) in dichloromethane (500 ml). Afterthe addition the ice-bath was removed and the mixture stirred for 1 hourwhen it was poured into ice-water (500 ml). The organic phase wasseparated and the aqueous portion extracted two times withdichloromethane. The combined dichloromethane extracts were washed withwater, then brine and dried (MgSO₄). The residue, after removal of thesolvent in vacuo and trituration with ether gave methyl 4-3-chloropropanoyl!phenoxyacetate, 22.3 g, as a solid: m.p. 89°-90° C.;NMR (d⁶ DMSO) δ 7.95(2H,d), 7.05(2H,d), 4.92(2H,s), 3.91(2H,t),3.71(3H,s), 3.49(2H,t); m/e 257(M+H)⁺ ; calculated for C₁₂ H₁₃ ClO₄ : C,56.1; H, 5.0. found: C, 55.8; H, 5.1%.

EXAMPLE 8 4- 3-!4-(4-Pyridyl)piperazin-1-yl!propanoyl!phenoxyacetic acid

In a similar manner to Example 2, but starting from the product ofExample 7, the title compound was prepared in 60% yield: m.p. 238°-239°C.; NMR (d⁶ DMSO+d⁴ acetic acid)δ 8.21(2H,d), 7.97(2H,d), 7.15(2H,d),7.02(2H,d), 4.77(2H,s), 3.64(4H,t), 3.21(2H,t), 2.82(2H,t), 2.62(4H,t);m/e 370(H+H)⁺ ; calculated for C₂₀ H₂₃ N₃ O₄ : C, 65.0; H, 6.3; N, 11.4.found C, 64.6; H, 6.4; N, 11.1%.

EXAMPLE 9 Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenylthioacetate

In a similar manner to Example 3, but starting from methyl4-bromoacetylphenylthioacetate, the title compound was prepared in 27%yield: m.p. 109°-110° C.; NMR (d⁶ DMSO) δ 8.15(2H,d), 7.93(2H,d),7.40(2H,d), 6.80(2H,d), 4.07(2H,s), 3.86(2H,s), 3.66(3H,s), 3.30(4H,t),2.61(4H,t); m/e 386 (M+H)⁺ ; calculated for C₂₀ H₂₃ N₃ O₃ S. 0.25 H₂ O:C, 61.4; H, 6.0; H, 10.7. found C, 61.8; H, 6.0; H, 10.6%.

The necessary starting material was prepared as follows:

Aluminium chloride (18.03 g) was added portionwise to a stirred cooled(<5° C.) solution of methyl phenylthioacetate (9.84 g) and bromoacetylchloride (4.46 ml) in dichloromethane (250 ml) keeping the temperaturebelow 5° C. The mixture was then stirred for one hour at ambienttemperature then poured onto ice. After a filtration, the organic phasewas separated and the aqueous portion extracted two times withdichloromethane. The combined dichloromethane extracts were washed withbrine, dried (MgSO₄), filtered and evaporated to give4-bromoacetylphenylthioacetate; 11.52 g, as a solid: m.p. 48°-50° C.;NMR (CDCl₃) δ 7.91(2H,d), 7.40(2H,d), 4.39(2H,s), 3.76(5H,s); m/e302/304 (M+H)⁺, 1Br pattern.

EXAMPLE 10 4- 2- 4-(4-Pyridyl)piperazin-1-yl!acetyl!phenylthioaceticacid

In a similar manner to Example 2, but starting from the product ofExample 9, the title compound was prepared in 83% yield: m.p. 240°-244°C.; NMR(d⁶ DMSO) δ 8.16(2H,d), 7.93(2H,d), 7.39(2H,d), 6.66(2H,d),3.92(2H,s), 3.86(2H,s), 3.38(4H,t), 2.64(4H,t); m/e 372(M+H)⁺ ;calculated for C₁₉ H₂₁ N₃ O₃ S. 0.25H₂ O: C, 60.6; H, 5.7; N, 11.2.found C, 60.5; H, 5.6; N, 10.8%.

EXAMPLE 11 Methyl 3- 2- 4-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenyl!propionate

A solution of methyl 3-(4-bromoacetylphenyl)propionate (380 mg) inacetonitrile (4 ml) was added dropwise over 15 minutes to a stirredsolution of 1-(4-pyridyl)piperazine (450 mg) in acetonitrile (10 ml) andthe mixture stirred overnight. The mixture was then filtered and thefiltrate concentrated in vacuo to give an oil. Purification by flashchromatography on silica eluting first with dichloromethane then 5% v/vmethanol/dichloromethane gave a solid. Trituration with ether gave thetitle compound, 172 mg, as a solid: m.p. 141°-143° C.; NMR(d⁶ DMSO) δ8.15(2H,d), 7.92(2H,d), 7.37(2H,d), 6.83(2H,d), 3.89(2H,s), 3.59(3H,s),3.37(4H,t), 2.93(2H,t), 2.69(2H,t), 2.65(4H,t); m/e 368(M+H)⁺ ;calculated for C₂₁ H₂₅ N₃ O₃. 0.25H₂ O: C, 67.8; H, 6.9; N, 11.3. found:C, 67.8; H, 6.9; N,11.1%.

EXAMPLE 12 3- 2- 4- 4-(4-Pyridyl)piperazin-1-yl!acetyl!phenyl!-propionicacid

A stirred solution of the product of Example 11 (70 mg) in methanol (0.5ml) was treated with a M sodium hydroxide solution (O.19 ml) andstirring continued for 3 hours. The methanol was removed in vacuo andthe residue diluted with water (1 ml), then a M hydrochloric acidsolution (0.19 ml) added. On cooling to 4° C. a solid precipitated whichwas collected, washed with ice-water, then dried to give the titlecompound, 36.5 mg: m.p. 245°-247° C.; NMR (d⁶ DMSO) δ 8.05(2H,d),7.91(2H,d), 7.36(2H,d), 6.86(2H,d), 3.89(2H,s), 3.34(4H,t), 2.87(2H,t),2.62(4H,t), 2.58(2H,t); m/e 354 (M+H)⁺ : calculated for C₂₀ H₂₃ N₃O₃.0.2 H₂ O: C, 67.2; H, 6.6; N, 11.8. found: C, 67.6; H, 6.6; N, 11.4%.

EXAMPLE 13 Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenylacetate

A solution of methyl 4-chloroacetylphenylacetate (260 mg) inacetonitrile (4 ml) was added dropwise over 15 minutes to a stirredsolution of 1-(4-pyridyl)piperazine (375 mg) in acetonitrile (10 ml) andthe mixture stirred overnight. The supernatent was decanted from thesolid formed, concentrated in vacuo and purified by flash chromatographyon neutral alumina, eluting with dichloromethane then 0.25% v/vmethanol/dichloromethane and finally 0.5% v/v methanol dichloromethane.Concentration of the fractions in vacuo gave the title compound, 96 mg,as a white crystalline solid: m.p. 127°-129° C.; NMR (d⁶ DMSO) δ8.15(2H,d), 7.98(2H,d), 7.41(2H,d), 6.81(2H,d), 3.91(2H,s), 3.78(2H,s),3.53(3H,s), 3.33(4H,t), 2.64(4H,t); m/e 354(M+H )⁺ ; calculated for C₂₀H₂₃ N₃ O₃ : C, 68.0; H, 6.6; N, 11.9. found: C, 68.2; H, 6.6; N, 11.9%.

EXAMPLE 14 Ethyl 4- 2- 4-(4-pyridyl)piperazin-1-yl!acetyl!-phenylacetate

Using a method similar to that of Example 13, but starting from ethyl4-chloroacetylphenylacetate and purification by flash chromatography onsilica, eluting with dichloromethane then 5% v/vmethanol/dichloromethane, the title compound was prepared in 13% yieldas solid: m.p. 122°-124° C.; NMR(d⁶ DMSO) δ 8.01(2H,d), 7.29(2H,d),7.25(2H,d), 6.67(2H,d), 3.93(2H,q), 3.75(2H,s), 3.60(2H,s), 3.18(4H,t),2.47(4H,t), 1.03(3H,t); m/e 368 (M+H)⁺ ; calculated for C₂₁ H₂₅ N₃ O₃ :C, 68.6; H, 6.9: N, 11.4. found: C, 68.2; H, 6.8; N, 11.3%.

EXAMPLE 15 4- 2- 4-(4-pyridyl)piperazin-1-yl!acetyl!phenylacetic acid,trifluoroacetate salt

A stirred solution of the product of Example 13 (142 mg) in methanol (1ml) was treated with M sodium hydroxide solution (0.46 ml) and stirringcontinued for 2 hours. The methanol was removed in vacuo, the residuediluted with water (1 ml), then a M hydrochloric acid solution (0.46 ml)was added. This solution was transferred to a 1 inch preparative reversephase hplc column (VYDAC^(R) 218TP1022) and eluted withwater/acetonitrile/trifluoroacetic acid in a gradient from 98:2:0.1v/v/v to 75:25:0.1 v/v/v. The pure fractions, on freeze-drying gave, thetitle compound 96 mg, as a foam: NMR (d⁶ DMSO) δ6 8.34(2H,d),7.95(2H,d), 7.48(2H,d), 7.25(2H,d), 4.67(2H,b), 3.93(4H,b), 3.72(2H,s),3.20(4H,b); m/e 340 (M+H)⁺ ; calculated for C₁₉ H₂₁ N₃ 03. 2.25 CF₃COOH: C, 47.4; H, 3.9; N, 7.1. found: C, 47.8; H, 3.8; N, 7.0%.

EXAMPLE 16 RS Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!-2-methyl-acetyl!phenoxyacetate

A solution of RS methyl 4-(2-methylacetyl)phenoxyacetate (1.2 g) inacetonitrile (10 ml) was added dropwise over 30 minutes to a stirredsolution of 1-(4-pyridyl)piperazine (1.3 g) in acetonitrile (30 ml) andthe mixture stirred overnight. The mixture was then filtered and thefiltrate evaporated to give an oil. Purification by flashchromatography, eluting first with dichloromethane then successively2.5%, 3%, 4%, 5% and 10% v/v methanol/dichloromethane gave the titlecompound, 220 mg as a solid: m.p. 81°-83° C.; NMR (d⁶ DMSO) δ8.13(2H,d), 8.06(2H,d), 7.02(2H,d), 6.77(2H,d), 4.92(2H,s), 4.33(1H,q),3.72(3H,s), 3.26(4H,t), 2.63(4H,t), 1.16(3H,d); m/e 384(M+H)⁺ ;calculated for C₂₁ H₂₅ N₃ O₄ : C, 65.8; H, 6.6; N, 11.0. found C, 65.7;H, 6.8; N, 10.9%.

EXAMPLE 17 RS 4- 2-4-(4-pyridyl)piperazin-1-yl!-2-methylacetyl!-phenoxyacetic acid sodiumchloride adduct dihydrate

A stirred solution of the product of Example 16, (110 mg) in methanol (1ml) was treated with a M sodium hydroxide solution (0.32 ml) andstirring continued overnight. The methanol was removed in vacuo and theresidue diluted with water and a M hydrochloric acid solution (0.32 ml)added. The solvent was removed in vacuo to give a yellow foam which, ontrituration with ether gave the title compound , 116 mg: NMR (D₆ DMSO) δ8.17 (2H,d), 8.06(2H,d), 7.01(2H,d), 6.98(2H,d), 4.76(2H,s), 4.37(1H,q),3.47(4H,t), 2.15(4H,t), 1.16(3H,d), m/e 370 (M+H)⁺ ; calculated for C₂₀H₂₃ N₃ O₄. NaCl. 2H₂ O: C, 51.8; H,5.8; N, 9.1. found: C,52.0; H, 5.6;N, 8.9%.

EXAMPLE 18 2,2'-4-(3-(4-(4-pyridyl)piperazin-1-yl!propanoyl!-phenylene-1,2-dioxy!diacetate,trifluoroacetate salt

Di-tertiary butyl 2,2'- 4-(3-4-(4-pyridyl)-piperazin-1-yl-propanoyl!phenylene-1,2-dioxy!diacetate(555 mg) was dissolved in 90% v/v trifluoroacetate acid/water (15 ml)and the mixture stirred for one hour. The solvent was removed byevaporation in vacuo and the residual oil on trituration with ether gavethe title compound, 608 mg, as a solid: m.p. 42°-44° C.; NMR (d⁶ DMSO) δ8.26(2H,d), 7.15(2H,d), 6.80(3H,m), 4.67(2H,s); 4.63(2H, s), 3.65(8H,b),3.39(1H,q), 2.75(2H,m), 2.66(2H,m), 1.09(1.5H,t); m/e 444 (M+H)⁺ ;calculated for C₂₂ H₂₅ N₃ O₇. 1.3 CF₃ COOH. 1H₂ O. 0.25 C₄ H₁₀ O: C,48.9; H, 4.9; N, 6.7. found C, 49.1; H, 5.0; N, 6.3%; calculated CF₃COOH; 23.6. found 23.2%.

The necessary starting material was prepared as follows:

(i) Solid sodium hydride (1.6 g of a 60% w/w dispersion in mineral oil)was added to a stirred, cooled (4° C.) solution of3,4-dihydroxybenzaldehyde (2.76 g) in THF (50 ml). The mixture was thenstirred for a further 15 minutes at ambient temperature, cooled to 4° C.when tertiary butyl bromoacetate (6.5 ml) was added followed by DMF (5ml). After one hour the mixture was diluted with ether (100 ml), washedwith water and brine, then dried (MgSO₄) and evaporated to give a solid.Recrystallisation from cyclohexane gave di-tertiary butyl 2,2'-(4-formyl!)phenylene-1,2-dioxy)diacetate, 4.1 g, as pale yellow crystals:m.p. 96° C.; NMR (d⁶ DMSO) δ 9.82(1H,s), 7.54(1H,dd), 7.33(1H,d),7.08(1H,d), 4.82(2H,s), 4.75(2H,s), 1.43(18H,s), m/e 366 (M+);calculated for C₁₉ H₂₆ O₇ ; C, 62.4; H, 7.3. found C, 62.3; H, 7.2%.

(ii) To a solution of the product of step (i) (10.0 g) and malonic acid(42 g) in pyridine (150 ml) was added a few drops of piperidine and themixture heated on a steam-bath for 4 hours. The pyridine was removed invacuo, water 300 ml added and the mixture extracted with ether (3-100ml). The combined extracts were washed with water, brine, dried (MgSO₄)then evaporated to give a gum. Recrystallisation from cyclohexane gavedi-tertiary butyl 2,2'-( 4-(3-propenoicacid)!phenylene-1,2-dioxy)diactate. 0.5 cyclohexane adduct, 6.6 g, m.p.104°-106° C.; NMR (d⁶ DMSO) δ 12.20(1H,b), 7.48(1H,d), 7.26(1H,s),7.20(1H,d), 6.89(1H,d), 6.40(1H,d), 4.74(2H,s), 4.72(2H,s), 1.43(18H,s),1.40(6H, s); m/e 408 (M+).

(iii) 10% w/w palladium on charcoal (250 mg) was added to a solution ofthe product of step (ii) (2.05 g) in ethyl acetate (100 ml) and themixture hydrogenated at room temperature and pressure untilthe-theoretical amount of hydrogen had been taken up. Charcoal wasadded, the mixture stirred for 5 minutes then filtered throughdiatomaneous earth and the filtrate evaporated to dryness givingdi-tertiary butyl 2,2'-(4-1-(2-carboxyethyl)!phenylene-1,2-dioxy)diacetate, 1.9 g, as a colourlessgum: NMR (CDCl₃)δ 6.76(3H,m), 4.58(2H,s), 4.56(2H,s), 2.86(2H,t),2.60(2H,t), 1.47(18H,s); m/e 410(M+). This gum slowly crystallised togive a white solid of m.p. 68°-70° C.; calculated for C21H₃₀ O₈ : C,61.5; H, 7.4. found: C,61.7; H, 7.7%.

To a stirred solution of the product of step (iii) (615 mg) in dry DMFwas added N,N'-diiosopropylethylamine (0.78 ml), HOBT (230 mg),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(596 mg). After 15 minutes 1-(4-pyridyl)piperazine (245 mg) was addedand stirring continued overnight. The DMF was removed in vacuo, theresulting oil partitioned between ethyl acetate (60 ml), and water (20ml). The organic phase was separated, washed successively with water (20ml), M sodium hydroxide solution (20 ml), brine (3×20 ml) then dried andthe solvent evaporated to give an oil. Purification of this oil by flashchromatography on silica, eluting with 6.5% v/v methanol indichloromethane gave di-tertiarybutyl 2,2'- 4- 3-4-(4-pyridyl)-piperazin-1-ylpropanoyl!phenylene-1,2-dioxy!-diacetate,728 mg, as a froth: m.p. 57°-61° C., NMR (d⁶ DMSO) δ 8.16(2H,d),6.80(5H,m), 4.63(2H,s), 4.59(2H,s), 3.58(4H,b), 3.32(4H,b), 2.73(2H,m),2.61(2H,m), 1.45(18H,s); m/e 556(M+H)⁺ ; calculated for C₃₀ H₄₁ N₃ O₇.0.5H₂ O: C, 63.8; H, 7.5; N, 7.4. found: C, 63.5; H, 7.4; N, 7.1%.

EXAMPLE 19 Methyl 2-S-(n-butylsulphonylamino)-3- 4-1-(4-pyridyl)-piperidin-4-yl!methoxyphenyl!propionate

n-Butylsulphonyl chloride (0.32 ml) was added dropwise to a solution ofmethyl 2-S-amino-3-4-(1-(4-pyridyl)piperidin-4-yl)methoxyphenyl!-propionate (750 mg) andtriethylamine (0.5 ml) in dichloromethane (15 ml) cooled in an ice bath.The mixture was allowed to reach ambient temperature and stirred for 5hours and then refluxed for 2 hours. The reaction mixture was washedwith water (20 ml) and saturated sodium chloride solution (15 ml) anddried (MgSO₄). The solvent was evaporated and the residue purified byflash chromatography eluting with methanol/dichloromethane (1:9v/v) togive the title compound (650 mg) as a gum; NMR(CDCl₃): 0.87(t,3H),1.26-1.7(m,6H), 1.95(d,2H), 2.1(m, 1H), 2.72-3.18(m,6H), 3.77(s,3H),3.79(d,2H), 3.96(d,2H), 4.32(m, 1H), 4.82(brd, 1H), 6.69(d,2H),6.83(d,2H), 7.1(d,2H), 8.25(brd,2H); mass spectrum (+ve FAB MeOH/NBA):490 (M+H)⁺ α!_(D) ²² =-14° C. (c=1, MeOH).

The starting material was prepared as follows:

(i) Diethylazodicarboxylate (0.58 ml) was added dropwise to a stirredmixture of 4-(4-hydroxymethylpiperidin-1-yl)pyridine (700 mg),N-benzyloxycarbonyl-S-tyrosine methyl ester (1.2 g), triphenylphosphine(955 mg) and THF (40 ml) in an atmosphere of argon and cooled to 10° C.The mixture was allowed to reach ambient temperature and stirred for 48hours. The solvent was removed by evaporation and the residue purifiedby flash chromatography eluting with methanol/dichloromethane (1:9v/v)to give methyl 2S-(benzyloxycarbonylamino)-3-4-(1-(4-pyridyl)piperidin-4-yl)methoxyphenyl!propionate (1.2 g) as asolid m.p. 68°-75° C.; NMR(d₆ -DMSO): 1.2-1.4(m,2H), 1.84(d,d,2H),1.92-2.1(m, 1H), 2.7-3.02(m,4H), 3.6(s,3H), 3.8(d,2H), 3.98(d,2H),4.14-4.28(m,1H), 4.98(s,2H), 6.78-6.88(m,4H), 7.13(d,2H),7.20-7.4(m,5H), 7.75(d,1H), 8.13(d,2H); mass spectrum (+ve FAB,MeOH/NBA): 504(M+H)⁺.

(ii) A solution of the product of step (i) (1 g) in ethanol (40 ml) and10% palladium/carbon (200 mg) was stirred in a stream of hydrogen for 4hours at ambient temperature. The mixture was filtered through a pad ofdiatomaceous earth and the solvent removed by evaporation to give methyl2-S-amino-3- 4-(1-(4'-pyridyl)piperidin-4-yl)-methoxyphenyl!propionateas an oil; NMR(d₆ DMSO): 1.13-1.44(m,2H), 1.75-2.13(m,3H),2.64-2.94(m,4H), 3.51(m, 1H), 3.57(s,3H), 3.81(d,2H), 3.96(d,2H),6.8(dd,2H), 6.83(d,2H), 7.08(d,2H), 8.12(dd,2H); mass spectrum(+ve FAB,MeOH/NBA): 370 (M+H)⁺.

EXAMPLE 20 2-S-(n-butylsulphonylamino)-3- 4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionic acid

Lithium hydroxide (285 mg) was added to a solution of the product ofExample 33 (520 mg) in a mixture of methanol (9 ml), THF (9 ml) andwater (9 ml) and stirred at ambient temperature for 3.75 hours. Thesolvent was evaporated and water (5 ml) added to the residue. A 10%aqueous solution of potassium hydrogen sulphate (8 ml) was added and anoil separated. The oil was dissolved in methanol and filtered throughdiatomaceous earth. The solvent was evaporated, and the residuetriturated with ethyl acetate gave the title compound 500 mg) as anamorphous solid, NMR (d₆ DMSO)): 0.81(t,3H), 1.1-1.6(m,6H), 1.85(d,2H),2.0(brs,1H), 2.58-3.0(m,6H), 3.68(t,2H), 3.8(d,2H), 3.98(d,2H),6.8(brs,4H), 7.13(d,2H), 8.12(brs,2H); mass spectrum(+ve FAB,methanol/m-nitrobenzyl alcohol(NBA) ): 476(M+H)⁺

EXAMPLE 21 Methyl 2-S-(n-butylsulphonylamino)-3- 4- 2-1-(4-pyridyl)-piperidin-4-yl!ethoxy!phenyl!propionate

n-Butylsulphonyl chloride (0.28 ml) was added dropwise to a solution ofmethyl 2-S-amino-3- 4- 2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!propionate (630 mg) andtriethylamine (0.5 ml) in dichloromethane (15 ml) cooled in an ice-bath.The mixture was allowed to reach ambient temperature and stirred for 5hours. The reaction mixture was diluted with dichloromethane (10 ml) andwashed with water (20 ml), saturated sodium chloride solution (10 ml)and dried (MgSO₄). The solvent was evaporated and the residue purifiedby flash chromatography eluting with methanol/dichloromethane(:9v/v) togive the title compound (680 mg) as a gum; NMR(CDCl₃): 0.9(t,3H),1.25-1.45(m,4H), 1.55-1.95(m,7H), 2.72-3.15(m,6H), 3.78(s,3H),3.9(brd,2H), 4.0(t,2H), 4.32(brs,1H), 4.84(brs,1H), 6.68(d,2H),6.83(d,2H), 7.09(d,2H), 8.23(brs,2H); mass spectrum(+ve FAB, MeOH/NBA):504 (M+H)⁺.

The starting material was prepared as follows:

(i) Following the method of Example 19, step (i), but using4-(4-hydroxyethylpiperidin-1-yl)pyridine, methyl2-S-(benzyloxycarbonylamino)-3- 4- 2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!-propionate (900 mg) wasprepared as an oil; NMR (d₆ DMSO): 1.05-1.35(m,2H), 1.6-1.9(m,5H),2.7-3.05(m,4H), 3.63(s,3H), 3.92(d,2H), 4.0(t,2H), 4.21(m,1H),4.98(s,2H), 6.8(d,2H), 6.84(d,2H), 7.14(d,2H), 7.3(m,4H), 7.75(d,1H),8.12(d,2H); mass spectrum(+ve FAB, NBA/CH₂ Cl₂): 518 (M+H)⁺.

(ii) Following the method of Example 19, step (ii), but using theproduct of step (i) above, methyl 2-S-amino-3- 4- 2-1-(4-pyridyl)-piperidin-4-yl!ethoxy!phenyl!propionate was prepared as agum; NMR(d₆ DMSO): 1.08-1.32(m,2H), 1.58-1.86(m,5H), 2.61-2.9(m,4H),3.52(m,1H), 3.58(s,3H), 3.82-4.02(m,4H), 6.79(dd,2H), 6.81(d,2H),7.07(d,2H), 8.1(dd,2H); mass spectrum(+ve FAB, MeOH/NBA): 384 (M+H)⁺.

EXAMPLE 22 2-S-(n-butylsulphonylamino)-3- 4- 2-1-(4-pyridyl)piperidin-4-yl!ethoxyl!phenyl!propionic acid

Following the method of Example 20, but using the product of Example 21the title compound (380 mg) was prepared; NMR(d₆ DMSO): 0.78(t,3H),1.05-1.5(m,6H), 1.6-1.9(m,5H), 2.5-3.05(m,6H), 3.8-4.05(m,6H),4.6(brs,1H), 6.85(m,4H), 7.19(d,2H), 8.13(brs,2H); mass spectrum(+veFAB, MeOH/NBA): 490 (M+H)⁺ ; microanalysis found: C, 57.7; H, 7.5; N,8.0; H₂ O, 7.1%; C₂₅ H₃₅ N₃ O 5S.2H₂ requires: C, 57.1; H, 7.4; N, 8.0;H₂ O, 6.9%.

EXAMPLE 23 Methyl 2-S-(n-butylsulphonylamino)-3- 4-1-(4-pyridyl)-piperidin-4-yl!oxyphenyl!propionate

Using a procedure similar to that described in Example 21, but startingfrom the appropriate amino acid ester, the title compound was-preparedNMR(CDCl₃): 0.9(t,3H), 1.25-1.45(m,2H), 1.55-1.8(m,2H), 1.8-2.15(m,4H),2.6-2.88(m,2H), 2.9-3.2(m,2H), 3.3-3.45(m,2H), 3.55-3.74(m,2H),3.78(s,3H), 4.27-4.4(m,1H), 4.45-4.6(m,1H), 4.8(brd,2H), 6.7(d,2H),6.86(d,2H), 7.1(d,2H), 8.26(brd,2H); mass spectrum (+ve FAB, MeOH/NBA):476 (M+H)⁺.

The starting material was prepared using similar procedures to thosedescribed in Example 21. There were thus prepared the followingintermediates starting from 4-(4-hydroxypiperidin-1-yl)pyridine:

Methyl 2-S-(benzyloxycarbonylamino)-3-4-(1-(4'-pyridyl)piperidin-4-yl)oxyphenyl!propionate; NMR(d₆ DMSO):1.5-1.72(m,2H), 1.9-2.1 (m,2H), 2.7-3.02(m,2H), 3.18(d,2H),3.2-3.35(m,1H), 3.48-3.77(m,1H), 3.62(s,3H), 4.13-4.28(m,1H),4.5-4.65(m,1H), 4.97(s,2H), 6.8-6.94(m,4H), 7.14(d,2H), 7.77(d,1H),8.15(d,2H); mass spectrum(+ve FAB, CH₂ Cl₂ /NBA): 518 (M+H)⁺.

Methyl 2-S-amino-3-4-(1-(4'-pyridyl)piperidin-4-yl)oxyphenyl!-propionate; NMR(d₆ DMSO):1.54-1.72(m,2H), 1.9-2.06(m,2H), 2.65-2.88(m,2H), 3.15-3.4(m,2H),3.52(t,1H), 3.59(s,3H), 3.6-3.75(m,2H), 4.52-4.65(m,1H), 6.8-6.92(m,4H),7.09(d,2H), 8.15(dd,2H); mass spectrum (+ve FAB, MeOH/NBA): 356 (M+H)⁺.

EXAMPLE 24 2-S-(n-butylsulphonylamino)-3- 4-1-(4-pyridyl)piperidin-4-yl!oxyphenyl!propionic acid

Using a similar procedure to that described in Example 20 but startingfrom the product of Example 23, the title compound was obtained as asolid m.p.255°-258° C. dec.; NMR(d₆ DMSO): 0.66 (t,3H), 0.98-1.04(m,2H), 1.05-1.4(m,2H), 1.44-1.62(m,2H), 1.8-1.96(m,2H), 2.49(t,2H),2.61(dd,1H), 2.87(dd,1H), 3.12-3.28(m,2H), 3.4-4.0(m,5H),4.43-4.55(m,1H), 6.79(m,4H), 7.09(d,2H), 8.04(brd,2H); mass spectrum(+veFAB, MeOH/NBA): 462 (M+H)⁺ ; microanalysis found: C, 59.6; H 6.9; N,9.0%; C₂₃ H₃₁ N₃ O₅ S requires: C, 59.8; H, 6.8; N, 9.1%.

EXAMPLE 25 Ethyl 4- 4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate

A stirred suspension of 4-(4-(4-pyridyl)piperazin-1-yl)-phenol (1.34 g)in dry DMF (20 ml) was treated with sodium hydride (60% dispersion inmineral oil, 0.21 g) and the mixture stirred for 1 hour. To theresulting solution was added ethyl 4-bromobutyrate and the mixture wasstirred for 16 hours. Solvent was evaporated under reduced pressure andthe residue was partitioned between ethyl acetate and water. The organiclayer was washed with water, filtered through phase separating paper(Whatman 1PS) and evaporated. The residue was purified by flashchromatography on silica, eluting with 1-5/92.5/6 v/v/v methanol/ethylacetate/aqueous ammonia (SG 0.89) and recrystallised from ethylacetate/hexane to give the title compound (0.7 g) as a solid: m.p.84°-85° C.; NMR (CDCl₃) δ 8.3(2H,d); 6.86(4H,c); 6.72(2H,d); 4.12(2H,q);4.0(2H,t); 3.47(4H,m); 3.20(4H,m); 2.5(2H,t); 2.1(2H,m); 1.26(3H,t); m/e370(M+H)⁺ ; calculated for C₂₁ H₂₇ N₃ O₃ C, 68.3; H, 7.4; N, 11.4.Found: C, 68.1; H, 7.4; N, 11.1%.

The necessary starting material was prepared as follows:

(i) 4-(piperazin-1-yl)anisole (4.24 g) and 4-chloropyridinehydrochloride (3.35 g) were intimately mixed and heated at 160°-170° C.(bath temperature) for 7 minutes. The solid obtained on cooling wasdissolved in water (75 ml) and the solution basified with aqueousammonia. The solid precipitate was extracted into ethyl acetate and theorganic extract washed with water, filtered through phase separatingpaper (Whatman 1PS) and evaporated. The residue was recrystallised fromethanol to give 4- 4-(4-pyridyl)-piperazin-1-yl!anisole (1.84 g) as asolid: m.p. 165°-167° C.; NMR (CDCl₃) δ8.3(2H,d); 6.86(4H,m);6.71(2H,d); 3.78(3H,s); 3.46(4H,m); 3.2(4H,m).

(ii) The product from step (i) (1.5 g) in concentrated hydrobromic acid(30 ml) was heated under argon at 130°-135° C. for 21/2 hours. Thesolution was cooled, poured into water (150 ml) and basified withaqueous ammonia. The precipitate was filtered, washed with water anddried to give 4- 4-(4-pyridyl)piperazin-1-yl!phenol (1.36 g) as a solid:m.p. 310°-312° C.; NMR(d₆ DMSO) δ 8.2(2H,d); 6.8(4H,m); 6.66(2H,d);3.45(4H,m); 3.08(4H,m).

EXAMPLE 26 4- 4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid

A solution of the product of Example 25 (0.1 g) in aqueous sodiumhydroxide (1N, 0.8 ml) and ethanol (2 ml) was kept for 2 hours. Thesolution was evaporated and the residue dissolved in water (5 ml).Hydrochloric acid (1N, 0.8 ml) was added and the precipitate wasfiltered and washed with water and ether to give the title compound as asolid: m.p 305°-306° C.; m/e 342(M+H)⁺ ; NMR(d₆ DMSO) δ 8.0(2H,d);6.72(6H,m); 3.74(2H,t); 3.3(4H,m); 2.94(4H,m); 2.19(2H,t); 1.72(2H, m);calculated for C₁₉ H₂₃ N₃ O₃ : C, 66.8; H, 6.8; N, 12.3. Found: C, 67.0;H, 6.8; N, 12.2%.

EXAMPLE 27 Ethyl 5- 4- 4-(4-Pyridyl)piperazin-1-yl!phenoxy!pentanoate

In a similar manner to Example 25, but starting from ethyl5-bromopentanoate, was prepared the title compound in 41% yield (fromethyl acetate/hexane): m.p. 79°-82° C.; NMR(CDCl₃) δ 8.2(2H,d),6.88(4H,m), 6.7(2H,d), 4.13(2H,q), 3.47(4H,m), 3.17(4H,m), 2.36(2H, m);1.8(4H,m), 1.33(3H,t); m/e 384(M+H)⁺ ; calculated for C₂₂ H₂₉ N₃ O₃.0.25H₂ O: C, 68.1; H, 7.6; N, 10.8. Found: C, 68.2; H, 7.8; N, 10.5%.

EXAMPLE 28 5- 4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!pentanoic acid

In a similar manner to Example 26, but starting from the product ofExample 27, the title compound was made in 50% yield: m.p. 237°-241° C.;NMR(d₆ DMSO) δ 8.2(2H,d); 6.97(4H,m), 6.83(2H,d); 3.69(2H,t),3.57(4H,m), 3.13(4H,m); 2.27(2H,t), 1.67(4H,m); m/e 356(M+H)⁺ ;calculated for C₂₀ H₂₅ N₃ O₃ 0.75H₂ O: C, 65.0; H, 7.2; N, 11.3. Found:C, 65.0; H, 6.9; N, 11.1%.

EXAMPLE 29 Ethyl 4- 4-(4-pyridyl)piperazin-1-yl!phenoxycrotonate

In a similar manner to Example 25, but starting from ethyl4-bromocrotonate, was prepared the title compound in 3% yield (fromethyl acetate/hexane): m.p. 127°-128° C.; NMR(CDCl₃) δ 8.3(2H,d),7.1(1H,m), 6.9(4H,m), 6.7(2H,m), 6.18(2H,m), 4.66(2H,m), 4.25(2H,q3.49(4H,m), 3.2(4H,m), 1.3(3H,t); m/e 368(M+H)⁺ ; calculated for C₂₁ H₂₅N₃ O₃ : C, 68.6; H, 6.9; N, 11.4. Found C, 68.4; H, 6.9; N, 10.7%.

EXAMPLE 30 Methyl 3- 4- 4-(4-pyridyl)piperazin-1-yl!!benzamidopropionate

Methyl 3-aminopropionate hydrochloride (0.195 g) and triethylamine (0.59ml) were added to a stirred suspension of 4-(4-pyridyl)piperazin-1-yl!benzoyl chloride hydrochloride (0.473 g) atroom temperature. The mixture was stirred for two days and solventremoved under reduced pressure. The residue was purified by flash columnchromatography. The product was obtained by elution with 1/9/0.1 v:v:vmethanol/dichloromethane/0.88 S.G. aqueous ammonia as a solid which wasrecrystallised from ethyl acetate to give the title compound (0.2 g):m.p. 197°-199° C.; NMR(d₆ DMSO) δ 8.19(2H,d); 7.72(2H,d); 7.13(2H,d);6.90(2H,d); 3.82(4H,m); 3.56(3H,s); 3.48(6H,m), 2.50(2H,t); m/e369(M+H)⁺ ; calculated for C₂₀ H₂₄ N₄ O₃. 0.25H₂ O: C,64.4; H, 6.6; N,15.0. Found: C,64.3; H, 6.6; N, 14.9%.

The necessary starting material was obtained as follows:

(i) An intimate mixture of 1-(4-pyridyl)piperazine (1.63 g) and4-bromobenzoic acid (1.05 g) was heated at 220° C. for 6 hours. Theresulting glass was cooled and triturated with methanol (50 ml) to give,as an off-white solid, 4-((4-pyridyl)piperazin-1-yl)benzoic acid;m.p>350° C.; IR(cm⁻¹) 1682, 1600, 1514, 1236, 1013.

(ii) Oxalyl chloride (0.5 ml) was added to a stirred suspension of4-((4-pyridyl)piperazin-1-yl)benzoic acid in dichloromethane (15 ml),followed by DMF (1 drop). The mixture was stirred for 2 hours andevaporated to dryness to give 4- (4-pyridyl)piperazin-1-yl!benzoylchloride which was used immediately.

EXAMPLE 31 3- 4- 4-(4-pyridyl)piperazin-1-yl!!benzamidopropionic acid

To a solution of the product of Example 30 (0.062 g) in methanol (1 ml)was added sodium hydroxide solution (1N, 0.17 ml) and the solution keptfor 4 days at room temperature. Hydrochloric acid (1N, 0.17 ml) wasadded to give the title compound as a solid (0.052 g); m.p. >330° C.;NMR(d₆ DMSO 6.96(2H,d); 3.76(4H,m); 3.46(6H, complex); 2.5(2H,m); m/e355 (M+H)⁺ ; calculated for C₁₉ H₂₂ N₄ O₃. 0.7 H₂ O: C, 62.2; H, 6.4; N,15.3. Found: C, 62.3; H, 6.4; N, 15.3%.

EXAMPLE 32 Methyl 3- 4-4-(4-pyridyl)piperazin-1-yl!benzamido!-3-phenylpropionate

In a similar manner to Example 36, but starting from methyl3-amino-3-phenylpropionate, was prepared the title compound in 26% yieldas a solid (after trituration with hot ethyl acetate); NMR(d₆ DMSO) δ8.6(1H,d); 8.2(1H,broad s); 7.75(2H,d); 7.3(5H,m); 7.0(2H,d); 6.85(2H,broad s); 5.45(1H,m); 3.55(3H,s); 3.45(8H,m); 292(2H,m); m/e 445(M+H)⁺ ;calculated for C₂₆ H₂₈ N₄ O3. 0.5H₂ O: C, 68.9; H, 6.4; N, 12.4. Found.C, 68.7; H, 6.3; N, 12.3%.

EXAMPLE 33 3- 4-4-(4-pyridyl)piperazin-1-yl!benzamido!-3-phenylpropionic acid

In a similar manner to Example 26, but starting from the product ofExample 32, was prepared the title compound in 73% yield as a solid;NMR(d₆ DMSO) δ 8.61(1H,d); 8.2(2H,broad s); 7.78(2H,d); 7.3(5H,m);7.0(2H,d); 6.9(2H,d); 5.43(1H,m); 3.45(8H,m); 2.82(1H,m); m/e 431(M+H)⁺; calculated for C₂₅ H₂₆ N₄ O₃ 0.5H₂ O: C, 68.3; H, 5.9; N, 12.8. Found:C, 68.3; H, 6.0; N, 12.9%.

EXAMPLE 34 ethyl 3- 4- 4-(4-pyridyl)piperazin-1-yl!benzamido!-butyrate

In a similar manner to Example 30, but starting from methyl3-aminobutyrate, was prepared the title compound in 11% yield(recrystallised from ethyl acetate/hexane) as a solid; m.p. 130°-132° C.NMR (d₆ DMSO) δ 8.28(2H,d); 8.07(1H,d); 7.77(2H,d); 7.13(2H,d);7.0(2H,d); 4.36(1H,m); 3.74(4H,m); 3.6(3H,s); 3.48(4H,m); 2.55(2H,m)1.2(3H,d); m/e 383(M+H)⁺ ; calculated for C₂₁ H₂₆ N₄ O₃. 0.25H₂ O: C,65.2; H, 6.9; N, 14.5. Found: C, 65.3; H, 6.8; N, 14.4%.

EXAMPLE 35 Methyl 4- 2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!-phenoxyacetate

A dispersion of potassium hydride in mineral oil (35% w/w, 0.63 g) wasadded to a stirred suspension of 4-(4-pyridyl)piperazin-2-one (0.885 g)in DMF (10 ml) and the mixture was stirred at room temperature for 2hours.

To the anion thus formed, was added methyl 4-bromoacetylphenoxyacetate(1.44 g) and the mixture was stirred at room temperature for 20 hours.Solvent was evaporated and the residue partitioned betweendichloromethane (20 ml) and water (20 ml). The organic layer was dried(MgSO₄) and evaporated. The residue was purified by flash columnchromatography, the product being eluted with 1/9/0.1 v:v:vmethanol/dichloromethane/0.88 S.G aqueous ammonia. Recrystallisationfrom ethyl acetate gave the title compound, m.p. 164°-165° C.; NMR(d₆DMSO) δ 8.2(2H,d), 7.97(2H,d), 7.08(2H,d), 6.83(2H,d), 4.93(4H,d),4.02(2H,s), 3.71(3H,s), 3.7(2H,m), 3.52(2H, m); m/e 384 (H+H)⁺ ;calculated for C₂₀ H₂₁ N₃ O₅ : C, 62.7; H, 5.52; N, 11.0. Found: C,62.6; H, 5.6; N, 10.9%.

The necessary starting material was prepared as follows:

An intimate mixture of piperazinone (4.2 g) and 4-chloropyridinehydrochloride (7.33 g) was stirred and heated at 200° C. for 10 minutesand allowed to cool. The product was purified by flash columnchromatography and eluted with 1/9/0.1 v:v:v methanol/methylenechloride/0.88 S.G. aqueous ammonia.

The solid thus obtained was recrystallised from ethanol to give4-(4-pyridyl)piperazin-2-one (1.75 g); m.p. 268°-270° C.; NMR(D₆ DMSO)δ8.2(3H,m); 6.8(12H,m); 3.85(2H,s); 3.52(2H,m); 3.31(2H,m); m/e178(M+H)⁺.

EXAMPLE 36 4- 2- 4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!-phenoxyacetic acid.

In a similar manner to Example 26, but starting from the product ofExample 35, was prepared the title compound in 20% yield as a solidNMR(d₆ DMSO) δ 8.22(2H,d), 7.97(2H,d), 7.04(2H,d), 6.89(2H,d);4.93(2H,s), 4.77(2H,s), 4.07(2H,s), 3.72(2H,m), 3.49(2H,m); m/e370(M+H)⁺); calculated for C₁₉ H₁₉ N₃ O5. 2.5H₂ O: C, 55.1; H, 5.8; N,10.1. Found: C, 55.1; H, 5.3; N, 10.6%.

EXAMPLE 37 Methyl 4- 4-(4-pyridyl)piperazin-1-yl!carboxamido!phenoxyacetate

To a solution of 1-(4-pyridyl)piperazine (0.4 g) in dichloromethane (10ml) was added a solution of methyl 4-isocyanatophenoxyacetate (0.5 g) indichloromethane (5 ml). The resulting solution was stirred for 3 hoursat room temperature. Solvent was evaporated and the residue trituratedwith ethanol to give the title compound as a solid (0.155 g); NMR(d₆DMSO) δ 8.55(1H,s), 8.22(2H,d), 7.28(2H,d), 7.02(2H,d), 6.82(2H,d),4.72(2H,s), 3.7(3HS), 3.58(8H,m); m/e 371(M+H)⁺ ; calculated for C₁₉ H₂₂N₄ O₄. H₂ O: C, 58.8; H, 6.2; N, 14.4 Found: C, 58.7; H, 5.8; N, 14.8%.

The necessary starting material was prepared as follows:

Methyl 4-aminophenoxyacetate (2.2 g) in ethyl acetate (dried withcalcium chloride) (50 ml) was added dropwise to a stirred solution ofphosgene in toluene (115 ml, .sup.˜ 2M) at 75° C. After addition themixture was stirred at 75° C. for 1.5 hours and at 95°-105° C. for 16hours. Solvent was evaporated to give an oil (2.5 g); 1R shows a strongband at 2273 cm⁻¹.

EXAMPLE 38 4- 4-(4-pyridyl)piperazin-1-yl!carboxamido!phenoxyacetic acid

In a similar manner to Example 26, but starting from the product ofExample 37, was prepared the title compound in 86% yield as a solid;NMR(d₆ DMSO) δ 8.45(1H,s); 8.2(2H,d), 7.35(2H,d), 6.35(4H,m),4.55(2H,s), 3.49(8H,m), m/e 357(M+H)⁺ ; calculated for C₁₈ H₂₀ N₄ O₄0.75 H₂ O: C, 58.5; H, 5.8; N, 15.2. Found: C, 58.5; H, 5.9; N, 15.1%.

EXAMPLE 39 Methyl 2-RS-(n-butylsulphonylamino)-3-(4- 2-4-(4-pyridyl)-piperazin-1-yl!acetyl!phenylpropionate

To a solution of 1-(4-pyridyl) piperazine (296 mg) and triethylamine(0.25 ml) in acetonitrile (10 ml) was added, dropwise, over 30 minutes asolution of methyl-2-RS-(n-butylsulphonylamino)-3-(4-bromoacetylphenyl)propionate (382 mg) in acetonitrile (8 ml). The mixture was stirred foran additional 4 hours. The solvent was removed by evaporation to give anoil which was purified by flash column chromatography on silica, elutingwith methanol/dichloromethane (5:95 to 10:90 v/v) to give the titlecompound as a solid (202 mg): NMR(d₆ DMSO) 0.7(t,3H), 1.05-1.4(m,4H),2.5-2.7(m,4H), 2.8-3.2(m,4H), 3.25-3.4(m,4H), 3.65(s,3H), 3.9(s,2H),4.1-4.25(m,1H), 6.85(d,2H), 7.45(d,2H), 7.95(d,1H), 7.95(d,2H),8.15(d,2H); m/e 503(M+H)⁺ ; calculated for C₂₅ H₃₄ N₄ O₅ S.O.5H₂ O: C,58.7; H, 6.85; N, 10.9. Found: C, 58.8; H, 6.9; N, 10.6.

The necessary starting material was prepared as follows:

(i) Methyl 2-amino-3-(4-acetylphenyl)propionate was prepared by themethod described by M. P. Doyle JOC (1977), 42, 2431 and G, H. ClelandJOC (1969), 34, 744.

(ii) n-Butylsulphonyl chloride(0.6 ml) was added dropwise over 15minutes to a solution of the product of step (i) (926 mg) andtriethylamine (0.7 ml) in dichloromethane (20 ml). The resulting mixturewas stirred for a further 3 hours before it was poured into water (10ml) and extracted with dichloromethane (3×20 ml). The organic extractswere combined, dried (MgSO₄) and then evaporated to give a gum.Purification by flash column chromatography on silica, eluting withethyl acetate/hexane (40:60 v/v) gave methyl2-RS-(n-butylsulphonylamino)-3-(4-acetylphenyl)propionate (794 mg) as asolid: NMR (d₆ DMSO) δ 0.75(t,3H), 1.0-1.4(m,4H), 2.55(s,3H),2.65(s,3H), 2.8.2.95(m,2H), 3.05-3.2(m,2H), 3.65(s,3H), 4.1-4.25(m,1H),7.45(d,2H), 7.85(d,1H), 7.9(d,2H); m/e 342(M+H)⁺.

(iii) To a suspension of CuBr₂ (822 mg) in ethyl acetate (8 ml) atreflux was added, dropwise over 10 minutes, a solution of the productfrom step (ii) in chloroform (8 ml). The resulting mixture was refluxedfor 3 hours. The mixture was cooled, filtered and the solvent wasremoved by evaporation to give an oil. Purification by flash columnchromatography on silica, eluting with ethyl acetate/hexane (10:90 to50:50 in 10% increments v/v) gave methyl2-RS-(n-butylsulphonylamino)-3-(4-bromoacetylphenyl) propionate (387 mg)as an oil: NMR (CDCl₃) δ 0.9(t,3H), 1.25-1.4(m,2H), 1.6-1.75(m,2H),2.75-2.85(m,2H), 3.05-3.3(m,2H), 3.8(s,3H), 4.35-4.45(m,1H), 4.4(s,2H),4.8(d,1H), 7.35(d,2H), 7.95(d,2H); m/e 420/422 (M+H)⁺, Br pattern.

EXAMPLE 40 2-RS-(n-butylsulphonylamino)-3- 4- 2-4-(4-pyridyl)-piperazine-1-yl!acetyl!phenyl!propionic acid

To a solution of the product of Example 39 (105 mg) in methanol (4 ml)was added 2N sodium hydroxide (0.25 ml) and the resulting solution wasstirred for 3 hour. The mixture was concentrated, dissolved in water (2ml) and acidified with acetic acid. The resulting solution wastransferred to a reverse phase hplc column (Dynamax C₁₈ 83 -201-C 60A)and eluted with 0.1% TFA in water/acetonitrile. The pure fractions, onfreeze drying, gave the title compound (89 mg) as a solid: NMR (d₆ DMSO)δ 0.8(t,3H), 1.15-1.6(m,4H), 2.75(t,2H), 2.9-3.05(m,1H), 3.2-3.3(m,1H),3.4-3.5(m,4H), 3.95-4.2(m,5H), 4.95(s,2H), 7.25(d,2H), 7.55(d,2H),8.0(d,2H), 8.35(d,2H); m/e 489(M+H)⁺ ; calculated for C₂₄ H₃₂ N₄ O₅ S.3CF₃ COOH: C, 43.4; H, 4.2; N, 6.7; TFA, 41.2. Found C, 43.7; H, 4.3; N,6.8; TFA, 42.7.

EXAMPLE 41 2-RS-(n-Butylsulphonylamino)-3- 4-(4-pyridyl)piperazin-1-ylmethylene!phenylpropionic acid

To a solution of ethyl 2-RS-(n-butylsulphonylamino)-3-4-(4-pyridyl)piperazin-1-yl methylene!phenylpropionate in methanol (3ml) was added 2N sodium hydroxide (0.3 ml). The mixture was stirred for3 hours and then concentrated. The resulting slurry was dissolved inwater (2 ml) and acidified with acetic acid. The resulting solution wastransfered to a reverse phase hplc column (Dynamax C₁₈ 83 -201-C 60 A)and eluted with 0.1% TFA in water/acetonitrile. The pure productfractions, on freeze drying, gave the title compound (165 mg) as asolid: NMR (d₆ DMSO) δ 0.8(t,3H), 1.1-1.6(m,4H), 2.65-2.95(m,4H),3.2-3.3(m,4H), 3.85-4.0(m,4H), 4.05-4.15(m,1H), 4.3(s,2H), 7.2(d,2H),7.4(s,5H), 8.3(d,2H); m/e 461(M+H)⁺ ; calculated for C₂₃ H₃₂ N₄ O₄ S.H₂O. 2CF₃ COOH: C, 45.9; H, 5.1; N, 7.9. Found C, 45.5; H, 4.8; N, 7.5.

The starting material was prepared as follows:

(i) To a solution of α,α'-dibromo-p-xylene (6.59g),N-(diphenylmethylene) glycine ethyl ester (4.76 g) and potassiumiodide in 1,4-dioxane (120 ml), cooled to 10° C., was added 40% aq.benzyltrimethylammonium hydroxide(7.45 ml) over 1 hour. The mixture wasallowed to warm to room temperature and thorn to stir for 2.5 hours. Themixture was partitioned between water (50 ml) and ethyl acetate (100ml). The organic layer was separated, dried (MgSO₄) and evaporated togive an oil. Purification by flash column chromatography on silica,eluting with ether/hexane (10:90 v/v) gave ethylRS-N-(diphenylmethylene)-4-(bromomethyl)phenylalanine ethyl ester (3.58g) as an oil: NMR (d₆ DMSO) δ 1.5(t,3H), 3.0-3.2(m,2H), 4.05-4.15(m,3H),4.65(s,2H), 6.55-6.65(m,2H), 7.0(d,2H),7.25(d,2H), 7.3-7.5(m,8H); m/e450/452(M+H)⁺ Br pattern.

(ii) To a warm solution of 1-(4-pyridyl)piperazine (296 mg) andtriethylamine (0.14 ml) in acetonitrile (15 ml) was added slowly over 40minutes a solution of the product from step (i) (409 mg) in acetonitrile(5 ml). The resulting mixture was stirred at room temperature for 18hours. The mixture was concentrated and purified by flash columnchromatography on silica, eluting with methanol/dichloromethane (3:97 to10:90 v/v) to give RS-N-(diphenylmethylene)-4-4-(4-pyridyl)piperazin-1-ylmethylene!phenyl-alanine ethyl ester (305 mg)as a solid: NMR (d₆ DMSO) δ 1.15(t,3H), 2.4-2.5(m,4H), 3.0-3.2(m,2H),3.25-3.35(m,4H), 3.45(s,2H), 4.05-4.15(m,3H), 6.65(d,2H), 6.75(d,2H),7.0(d,2H), 7.15(d,2H), 7.35-7.5(m,8H), 8.1(d,2H); m/e 533(M+H)⁺.

(iii) To a suspension of the product from step (iii) in ether (5 ml) wasadded 1N hydrochloric acid (2.2 ml) and the resulting mixture wasstirred for 1 hour. The mixture was partitioned between ether (20 ml)and 1N hydrochloric acid(10 ml). The acid layer was separated basifiedwith aqueous sodium bicarbonate and extracted dichloromethane (3-20 ml).The organic extracts were combined, dried (MgSO₄) and evaporated to giveRS-4- 4-(4-pyridyl)-piperazin-1-ylmethylene!phenylalanine ethyl ester asan oil: NMR (d₆ DMSO) δ 1.1 (t,3H), 2.4-2.5(m,4H), 2.7-2.9(m,2H),3.2-3.35(m,4H), 3.5(s,2H), 3.5-3.6(m,1H), 4.0(q,2H), 6.8(m,2H),7.2(dd,4H), 8.1(bm,2H); m/e 369 (M+H )⁺.

(iv) To a solution of the product of step (iii) (137 mg) andtriethylamine (0.11 ml) in tetrahydrofuran (8 ml) was added 0.75 ml of astock solution of n-butylsulphonyl chloride (0.2 ml in 3 ml oftetrahydrofuran) and the resulting mixture was stirred for 3 hours. Thesolvent was removed by evaporation to give a gum. Purification by flashcolumn chromatography on silica, eluting with methanol/dichloromethane(5:95 to 10:90 v/v) gave ethyl 2-(RS)-(n-butylsulphonylamino)-3-4-(4-pyridyl)piperazin-1-yl-methylene!phenylpropionate as a solid whichwas used without further purification.

EXAMPLE 42 4- 4-(4-pyridyl)piperazin-1-yl!methylene!cinnamic acid

^(t) Butyl 4- 4-(4-pyridyl)piperazin-1-yl!methylene! cinnamate (200 mg)was stirred in trifluoroacetic acid (5 ml) for 2 hours. The solvent wasremoved by evaporation and the resulting oil was titriated withanhydrous ether to give the title compound (210 mg) as a white solid:NMR (d₆ DMSO) δ 3.05-3.25(m,4H), 3.7-4.1(bm,4H), 4.25(s,2H), 6.6(d,1H),7.25(d,2H), 7.5(d,2H), 7.6(d,1H), 7.75(d,2H), 8.35(d,2H); m/e 324(M+H)⁺; calculated for C₁₉ H₂₁ N₃ O₂.2CF₃ COOH.0.5H₂ O: C, 49.5; H, 4.25; N,7.4. Found: C, 49.1; H, 4.2; N, 7.1.

The necessary starting material was prepared as follows:

(i) In a similar to Example 39, but starting from ^(t) butyl4-bromomethyl cinnamate was prepared ^(t) butyl 4-4-(4-pyridyl)-piperazin-1-yl!methylene! cinnamate: NMR (d₆ DMSO) δ1.45(s,9H), 3.55(s,2H), 6.5(d,1H), 6.8(d,2H), 7.35(d,2H), 7.55(d,1H),7.65(d,2H), 8.15(d,2H).

EXAMPLE 43 Dimethyl 4- 2-(4-(4-pyridyl)piperazin-1-yl)-2-methyl!-acetyl!-1,2-diphenoxydiacetate

In a similar manner to Example 39, but starting from dimethyl 4-(2'-bromopropionyl)-phenylene-1,2-dioxy!diacetate was prepared the titlecompound: NMR (d₆ DMSO) δ 1.15(d,3H), 2.55-2.7(m,4H), 3.2-3.35(m,4H),3.68(s,3H),3.70(s,3H), 4.25(q,1H), 4.9(s,2H), 4.95(s,2H), 6.75(d,2H),7.0(d,1H), 7.65(d,1H), 7.75(dd,1H), 8.15(d,2H); m/e 472(M+H)⁺.

The starting material was prepared as follows:

(i) To a solution of 3,4 dihydroxypropiophenone (1.24 g) in DMF (15 ml)was added anhydrous potassium carbonate (3.09 g) followed by methylbromoacetate (1.4 ml). The resulting mixture was stirred for 24 hours.Water (50 ml) was added and the mixture was extracted with ethyl acetate(3×100 ml). The organic extracts were combined, dried (MgSO₄) andevaporated to give a gum. Purification by flash column chromatography onsilica, eluting with ethyl acetate/hexane (1:1 v/v) gave dimethyl4-propionyl-phenylene-1,2-dioxydiacetate (1.79 g) as an oil: NMR (d₆DMSO) δ 1.05(t,3H), 3.0(q,2H), 3.7(s,6H), 4.9(s,2H),4.95(s,2H),7.05(d,d,1H), 7.45(d,1H), 7.6(dd,1H),; m/e 311(M+H)⁺.

(ii) To a solution of the product from step (i) (1.79 g) in chloroform(15 ml) was added dropwise a solution of bromine (0.3 ml) in chloroform(5 ml) and the resulting mixture was stirred for 3 hours. The solventwas removed by evaporation to give a gum which was purified by flashcolumn chromatography on silica, eluting with ethyl acetate/hexane (2:3v/v) to give dimethyl 4-(2'-bromopropionyl)-phenylene-1,2-dioxy)diacetate (1.95 g), whichsolidified on standing: NMR (d₆ DMSO) δ 1.75(d,3H), 3.7(s,6H),4.9(s,2H), 4.95(s,2H), 5.8(q,1H), 7.05(d,1H), 7.5(d,1H), 7.7(dd,1H); m/e389/391 (N+H)⁺ Br pattern.

EXAMPLE 44 4- 2-(4-pyridyl)piperazin-1-yl!-2-methyl!acetyl-1,2-diphenoxydiacetic acid

In a similar manner to Example 40, but starting from the product ofExample 43 was prepared the title compound: NMR (d₆ DMSO) δ 1.4(d,3H),3.0-3.2(m,4H), 3.75-3.9(m,4H), 4.75-5.0(m,1H), 4.8(s,2H), 4.85(s,2H),7.05(d,1H), 7.25(d,2H), 7.55(d,1H), 7.75(dd,1H), 8.3(d,2H); m/e444(M+H)⁺. Calculated for C₂₂ H₂₅ N₃ O₇.2.25CF₃ COOH.H₂ O C, 4.3; H,4.1; N, 5.85; TFA, 35.7. Found C, 44.2; H, 3.9; N, 5.7; TFA, 36.2.

EXAMPLE 45 Methyl 2-S-(n-butylsulphonylamino)-3- 4- 3-1-(4-pyridyl)-piperidin-4-yl!propoxy!phenyl!propionate.

Using a procedure similar to that described in Example 21, but startingfrom the appropriate amino ester, the title compound was prepared;NMR(d₆ DMSO): 0.75(t,3H), 1.0-1.44(m,8H), 1.44-1.64(m,1H), 1.75(brd,4H),2.5-3.02(m,6H), 3.64(s,3H), 3.85-4.1(m,5H), 6.81(d,2H), 6.84(d,2H),7.19(d,2H), 7.78(d,1H), 8.12(d,2H); mass spectrum(+ve FAB, MeOH/NBA):518 (M+H)⁺.

The starting material was prepared using similar procedures to thosedescribed in Example 19. There was thus prepared the followingintermediates (i) and (ii) which were themselves prepared starting from4-(4-hydroxypropylpiperidin-1-yl) pyridine(iii).

(i) Methyl 2-S-(benzyloxycarbonylamino)-3- 4- 3-1-(4-pyridyl)piperidin-4-yl!propoxy!phenyl!propionate; NMR(d₆ DMSO):1.18-1.24(m,2H), 1.3-1.43(m,2H), 1.44-1.65(m,1H), 1.65-1.83(m,4H),2.7-2.88(m,3H), 2.96(dd,1H), 3.61(s,3H), 3.92(t,4H), 4.14-4.25(m,1H),4.98(s,2H), 6.8(d,2H), 6.82(d,2H), 7.14(d,2H), 7.2-7.4(m,5H),7.74(d,1H), 8.12(d,2H); mass spectrum(+ve FAB, MeOH/NBA): 532(M+H)⁺.

(ii) Methyl 2-S-amino-3- 4- 3-1-(4pyridyl)piperidin-4-yl!-propoxy)phenyl!propionate; NMR(d₆ DMSO):1.03-1.2(m,2H), 1.28-1.40(m,2H), 1.42-1.62(m,1H), 1.64-1.80(m,4H),2.65-2.9(m,4H), 31.58(s,3H), 3.45-3.6(m,1H), 3.85-3.98(m,4H),6.78(d,2H), 6.8(d,2H), 7.06(d,2H), 8.11(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 398(M+H)⁺.

(iii) 4-(4-Hydroxypropylpiperidin-1-yl)pyridine.

A solution of N-(2-carbamoylethyl)-4-cyanopyridinium chloride (2.1 g) inwater (5 ml) was added dropwise to a stirred mixture of4-hydroxypropylpiperidine (2.4 g), water (10 ml) and 2.5M sodiumhydroxide solution (4.6 ml) cooled in an ice-bath. The mixture wasstirred at 0°-5° C. for 1 hour. 2.5M sodium hydroxide solution (7 ml)was added and the mixture heated at reflux for 3 hours. The mixture wascooled in an ice-bath and gummy solid separated out. The aqueous layerwas decanted off and the gummy solid dissolved in dichloromethane (75ml). The solution was washed with saturated sodium chloride solution (10ml) and dried (MgSO₄). The solvent was removed by evaporation to give agummy solid (880 mg) which on trituration with ether gave a solid;NMR(d₆ DMSO): 1.0-1.35(m,4H), 1.35-1.6(m,3H), 1.7(dd,2H),2.70-2.88(dt,2H), 3.38(t,2H), 3.89(brd,2H), 4.35(brs,1H), 6.78(d,2H),8.1(d,2H); mass spectrum(CI⁺): 221(M+H)⁺.

EXAMPLE 46 2-S-(n-butylsulphonylamino)-3- 4- 3-1-(4-pyridyl)-piperidin-4-yl!propoxy!phenyl!propionic acid.

Using a similar procedure to that described in Example 20, but startingfrom the product of Example 45, the title compound was obtained as anamorphous solid; NMR(d₆ DMSO/CD₃ CO₂ D): 0.73(t,3H), 1.0-1.5(m,8H),1.55-1.85(m,5H), 2.54-2.78(m,3H), 2.9-3.2(m,3H), 3.8-3.98(m,3H),4.15(brd,2H), 6.8(d,2H), 7.09(d,2H), 7.15(d,2H), 8.1(d,2H); massspectrum(+ve FAB, MeOH/NBA): 504(M+H)⁺ ; microanalysis found C,60.3;H,7.2; N,7.9%; C₂₆ H₃₇ N₃ O₅ S.H₂ O requires C,59.9; H,7.5; N,8.1%.

EXAMPLE 47 Methyl 2-S-(butylsulphonylamino)-3- 4- 4-1-(4-pyridyl)piperidin-4-yl!butoxy!phenyl!propionate.

Using a similar procedure to that described in Example 21, but startingfrom the appropriate amino ester, the title compound was prepared;NMR(CDCl₃): 0.87(t,3H), 1.14-1.4(m,6H), 1.42-1.7(m,5H), 1.7-1.9(m,4H),2.7-3.18(m,6H), 3.78(s,3H), 3.9(brd,2H), 3.93(t,2H), 4.32(brs,1H),4.82(brs,1H), 6.66(d,2H), 6.83(d,2H), 7.09(d,2H), 8.22(d,2H); massspectrum(+ve FAB, MeOH/NBA): 532 (M+H)⁺.

The starting material was prepared using similar procedures to thosedescribed in Example 19 and 45(iii). There was thus prepared thefollowing intermediates:

(i) 4-(4-hydroxybutylpiperidin-1-yl)pyridine; NMR(d₆ DMSO):0.97-1.58(m,9H), 1.7(dd,2H), 2.78(dt,2H), 3.38(m,2H), 3.88(brd,2H),4.29(t,1H), 6.78(d,2H), 8.10(d,2H); mass spectrum(CI⁺): 235(M+H)⁺.

(ii) Methyl 2-S-(benzylcarbonylamino)-3- 4- 4-1-(4-pyridyl)-piperidin-4-yl!butoxy!phenyl!propionate; NMR(d₆ DMSO):1.0-1.35(m,4H), 1.35-1.60(m,3H), 1.62-1.80(m,4H), 2.8(dt,3H),2.96(dd,1H), 3.62(s,3H), 3.85-3.97(m,4H), 4.15-4.28(m,1H), 4.99(s,2H),6.78(d,2H), 6.81(d,2H), 7.13(d,2H), 7.2-7.4(m,5H), 7.74(d,1H),8.11(d,2H), mass spectrum(CI⁺): 546(M+H)⁺.

(iii) Methyl 2-S-amino-3- 4- 4-1-(4-pyridyl)-piperidin-4-yl!-butoxy!phenyl!propionate; NMR(d₆ DMSO):1.05-1.35(m,4H), 1.35-1.58(m,3H), 1.6-1.8(m,4H), 2.65-2.9(m,4H),3.51(t,1H), 3.58(s,3H), 3.8-3.98(m,4H), 6.78(dd,2H), 6.81(d,2H),7.05(d,2H), 8.1(dd,2H); mass spectrum(CI⁺): 412(M+H)⁺.

EXAMPLE 48 2-S-(n-butylsulphonylamino)-3- 4- 4-1-(4-pyridyl)-piperidin-4-yl!butoxy!phenyl!propionic acid.

Using a similar procedure to that described in Example 20 but startingfrom the product of Example 47, the title compound was obtained as anamorphous solid; NMR(d₆ DMSO): 0.78(t,3H), 1.0-1.6(m,11H),1.6-1.82(brt,4H), 2.5-3.04(m,6H), 3.8-4.0(m,5H), 6.8(m,4H), 7.19(d,2H),8.1(brd,2H); mass spectrum(+ve FAB,MeOH/NBA): 518(M+H)⁺ ; microanalysisfound C,62.4; H,7.8; N,7.9%; C₂₇ H₃₉ N₃ O₅ S requires C,62.6; H,7.6;N,8.1%.

EXAMPLES 49-51

Using a procedure similar to that described in Example 21, but startingfrom the appropriate substituted sulphonyl chloride and methyl2-S-amino-3- 4- 2- 1-(4-pyridyl)piperidin-4-yl!ethoxy!-phenyl!propionatethere was obtained the following compounds:

EXAMPLE 49 Methyl 2-S-(methylsulphonylamino)-3- 4-2-(4-pyridyl)-piperidin-4-yl!ethoxy!phenylpropionate.

NMR(d₆ DMSO): 1.08-1.34(m,2H), 1.6-1.85(m,5H), 2.6(s,3H), 2.7-3.0(m,4H),3.63(s,3H), 3.84-4.2(m,5H), 6.80(d,2H), 6.85(d,2H), 7.18(d,2H),8.12(d,2H); mass spectrum(+ve FAB, MeOH/NBA): 462(M+H)⁺.

EXAMPLE 50 Methyl 2-S-(benzylsulphonylamino)-3- 4- 2-1-(4pyridyl)-piperidin-4-yl!ethoxy!phenyl!propionate

NMR(d₆ DMSO): 1.05-1.28(m,2H), 1.57-1.82(m,5H), 2.68.2.95(m,4H),3.58(s,3H), 3.8-4.15(m,7H), 6.79(d,2H), 6.88(d,2H), 7.12(d,2H),7.17(m,2H), 7.3(m,3H), 7.79(brd,1H), 8.1(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 538(M+H)⁺.

EXAMPLE 51 Methyl 2-S-(4-methylphenylsulphonylamino)-3- 4- 2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!propionate

NMR(d₆ DMSO): 1.1-1.33(m,2H), 1.6-1.88(m,5H), 2.35(s,3H),2.6-2.75(dd,1H), 2.75-2.92(m,3H), 3.38(s,3H), 3.8-4.1(m,5H), 6.76(d,2H),6.81(d,2H), 7.0(d,2H), 7.28(d,2H), 7.47(d,2H), 8.12(d,2H), 8.32(d,1H);mass spectrum(+ve FAB, MeOH/NBA): 538(M+H)⁺.

EXAMPLES 52-54

Following the method of Example 20, but using the products of Examples49-51, there was obtained the following compounds:

EXAMPLE 52 2-S-Methylsulphonylamino-3- 4- 2-1(4-pyridyl)-piperidin-4-yl!ethoxy!phenyl!propionic acid

NMR(d₆ DMSO): 1.05-1.35(m,2H), 1.6-1.95(m,5H), 2.61(s,3H),2.65-3.1(m,4H), 3.88-4.1(m,5H), 6.84(d,2H), 6.9(d,2H), 7.18(d,2H),8.14(d,2H); mass spectrum(+ve FAB, MeOH/NBA): 448(M+H)⁺.

EXAMPLE 53 2-S-Benzylsulphonylamino-3- 4- 2-1-(4-pyridyl)-piperidin-4-yl!ethoxy!phenyl!propionic acid

NMR(d₆ DMSO/CD₃ CO₂ D): 1.07-1.35(m,2H), 1.60-1.88(m,5H), 2.7-3.2(m,4H),3.85-4.25(m,7H), 6.87(d,2H), 7.1(d,2H), 7.13-7.45(m,7H), 8.15(d,2H);mass spectrum(+ve FAB,MeOH/NBA): 524(M+H)⁺ ; microanalysis found C,61.8;H,6.8; N,7.6%; C₂₈ H₃₃ N₃ O₅ S.H₂ O requires C,62.1; H,6.5; N,7.8%.

EXAMPLE 54 Lithium 2-S-(4-methylphenylsulphonylamino)-3- 4- 2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!propionate

NMR(d₆ DMSO/CD₃ CO₂ D): 1.15-1.38(m,2H), 1.67-1.78(m,2H),1.82-2.0(m,3H), 2.36(s,3H), 2.65-2.8(dd,1H), 2.85-2.95(dd,1H),3.14(t,2H), 3.78(m,1H), 4.0(t,2H), 4.18(d,2H), 6.77(d,2H), 7.04(d,2H),7.11(d,2H), 7.24(d,2H), 7.51(d,2H), 8.15(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 536(M+Li)⁺ ; microanalysis found C,63.2; H,6.5; N,7.9%; C₂₈H₃₂ N₃ O₅ SLi requires C,63.5; H,6.1; N,7.9%.

EXAMPLE 55 Methyl 2-S-(pentanoylamino)-3- 4- 2-1-(4-pyridyl)-piperidin-4-yl!ethoxy!phenyl!propionate.

Valeryl chloride (0.25 ml) was added dropwise to a solution of methyl2-S-amino-3- 4- 2- 1-(4-pyridyl)piperidin-4-yl!ethoxy!-phenyl!propionate(640 mg) and triethylamine (0.7 ml) in dichloromethane (17 ml) atambient temperature. The reaction mixture was stirred for 5 hours andthen diluted with dichloromethane (20 ml) and washed with water (20 ml),saturated sodium chloride solution (10 ml) and dried (MgSO₄). Thesolvent was evaporated and the residue purified by flash chromatographyeluting with methanol/dichloromethane (1:9 v/v) to give the titlecompound (660 mg) as a gum; NMR(d₆ DMSO): 0.81(t,3H), 1.05-1.3(m,4H),1.3-1.45(m,2H), 1.60-1.85(m,5H), 2.04(t,2H), 2.7-3.0(m,4H), 3.6(s,3H),3.92(d,2H), 3.99(t,2H), 4.35-4.48(m,1H), 6.8(d,2H), 6.83(d,2H),7.11(d,2H), 8.12(d,2H), 8.18(d,1H); mass spectrum(+ve FAB,MeOH/NBA):468(M+H)⁺.

EXAMPLE 56 Methyl 2-S-(pentanoylamino)-3- 4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionate.

Using a procedure similar to that described in Example 55, but startingfrom the appropriate amino ester, the title compound was prepared,NMR(d₆ DMSO): 0.8(t,3H), 1.05-1.45(m,6H), 1.83(dd,2H), 1.9-2.1(m,1H),2.04(t,2H), 2.7-3.0(m,4H), 3.59(s,3H), 3.82(d,2H), 3.96(d,2H),4.35-4.48(m,1H), 6.80(d,2H), 6.83(d,2H), 7.10(d,2H), 8.12(d,2H),8.17(d,1H); mass spectrum(+ve FAB, MeOH/NBA): 454(M+H)⁺.

EXAMPLE 57 2-S-(Pentanoylamino)-3- 4- 2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!propionic acid.

Using a procedure similar to that described in Example 20, but startingfrom the product of Example 55, the title compound was prepared, NMR(d₆DMSO): 0.8(t,3H), 1.08-1.3(m,4H), 1.3-1.45(m,2H), 1.6-1.87(m,5H),2.05(t,2H), 2.7-3.05(m,4H), 3.9-4.05(m,4H), 4.3-4.43(m,1H), 6.82(d,2H),6.85(d,2H), 7.11(d,2H), 7.97(d,1H), 8.12(brd,2H); mass spectrum(+ve FAB,MeOH/NBA): 454(M+H)⁺ ; microanalysis found C,63.1; H,7.8; N,8.3%; C₂₆H₃₅ N₃ O₄.2H₂ O requires C,63.8; H,8.0; N,8.6%.

EXAMPLE 58 2-S-(Benzyloxycarbonylamino)-3- 4- 2-1-(4-pyridyl)piperidin-4-yl!ethoxy!phenyl!propionic acid.

Using a procedure similar to that described in Example 20, but startingfrom the product of Example 35, step (i), the title compound wasprepared, NMR(d₆ DMSO): 1.1-1.35(m,2H), 1.6-1.9(m,5H), 2.65-3.1(m,4H),3.85-4.2(m,5H), 4.96(s,2H), 6.75-6.9(m,4H), 7.14(d,2H), 7.2-7.35(m,5H),7.5(d,1H), 8.1(d,2H); mass spectrum(+ve FAB, MeOH/NBA): 504(M+H)⁺.

EXAMPLE 59 Methyl-2-S-(n-butylsulphonylamino)-3-3-(N-methyl-N-4-pyridyl)aminopropoxy!phenylpropionate.

Using a procedure similar to that described in Example 19, but startingfrom methyl 2-S-amino-3-3-(N-methyl-N-4-pyridyl)-aminopropoxy!phenylpropionate, the titlecompound was prepared, NMR(CDCl₃): 0.89(t,3H), 1.25-1.4(m,2H),1.55-1.75(m,2H), 2.0-2.15(m,2H), 2.80(dd,2H), 2.9-3.15(m,2H),3.05(s,3H), 3.63(t,2H), 3.77(s,3H), 3.95(t,2H), 4.28-4.38(m,1H),6.57(d,2H), 6.80(d,2H), 7.10(d,2H), 8.14(d,2H); mass spectrum (CI³⁰):464(M+H)⁺.

The necessary starting material was prepared as follows:

(i) Using a procedure similar to that described in Example 19, step (i),but starting from N-methyl-N-(4-pyridyl)aminopropanol andN-t-butyloxycarbonyl-S-tyrosine methyl ester, there was obtained, methyl2-S-(t-butyloxycarbonylamino)-3-3-N-methyl-N-(4-pyridyl)-aminopropoxy!phenyl propionate, as a gum,NMR(CDCl₃): 1.43(s,9H), 2.0-2.15(m,2H), 3.04(s,3H), 2.95-3.10(m,2H),3.62(t,2H), 3.73(s,3H), 3.98(t,2H), 4.54(brd,1H), 4.98(brd,1H),6.56(d,2H), 6.80(d,2H), 7.04(d,2H), 8.17(d,2H).

(ii) The product from step (i) (500 mg) and 5M methanolic hydrochloricacid solution (4 ml) was stirred at ambient temperature for 16 hours.The solvent was evaporated to give the corresponding amino compound asthe dihydrochloride salt which was used without further purification.

EXAMPLE 60 2S-(n-Butylsulphonylamino)-3-3-(N-4-pyridyl-N-methyl)aminopropoxy!phenyl propionic acid

Using a procedure similar to that described in Example 20, but startingfrom the product of Example 59, the title compound was prepared, NMR(d₆DMSO/CD₃ CO₂ D): 0.8(t,3H), 1.1-1.28(m,2H), 1.28-1.55(m,2H),2.0-2.15(m,2H), 2.6-2.8(m,3H), 2.93-3.08(dd,1H), 3.18(s,3H), 3.75(t,2H),3.9-4.05(m,3H), 6.86(d,2H), 7.0(d,2H), 7.2d,2H), 8.15(d,2H); massspectrum (+ve FAB,MeOH/NBA): 450(M+H)⁺ ; microanalysis found C,53.9;H,6.9; N,8.4%; C₂₂ H₃₁ N₃ O₅ S.2H₂ O requires C,54.4; H,7.2; N,8.6%.

EXAMPLE 61 Methyl 3-(n-butylsulphonylamino)-3- 4- 1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionate.

Using a procedure similar to that described in Example 19, but startingfrom methyl 3-amino-3- 4-1-(4-pyridyl)piperidin-4-yl!-methoxyphenyl!propionate, dihydrochloride,the title compound was prepared; NMR(CDCl₃): 0.84(t,3H), 1.2-1.4(m,2H),1.4-1.55(m,2H), 1.55-1.75(m,2H), 1.97(brd,2H), 2.02-2.2(m,1H),2.65-2.85(m,2H), 2.88(d,2H), 3.0(dt,2H), 3.67(s,3H), 3.84(d,2H),4.0(brd,2H), 4.85(q,1H), 5.40(d,1H), 6.71(d,2H), 6.86(d,2H), 7.27(d,2H),8.25(d,2H); mass spectrum(+ve FAB,MeOH/NBA): 490(M+H)⁺.

The starting material was prepared as follows:

(i) Thionyl chloride (4.3 ml) was added to methanol (50 ml) cooled in anice-salt bath. 3-Amino-3-(4-hydroxyphenyl)propionic acid (9.7 g) wasadded and the mixture allowed to reach ambient temperature and thenrefluxed for 2 hours. The solvent was removed by evaporation in vacuo togive a gummy solid (12.8 g) which was used without further purification.A solution of di-t-butyldicarbonate (5.8 g) in dichloromethane (50 ml)was added to a stirred mixture of the gummy solid (5.75 g) and potassiumhydrogen carbonate (6.2 g) in water (20 ml). The mixture was stirred atambient temperature for 4 hours. The organic layer was separated andwashed with water (10 ml), 1M hydrochloric acid solution (10 ml),saturated sodium hydrogen carbonate solution (10 ml), water (10 ml) anddried (MgSO₄). The solvent was evaporated to give methyl3-(t-butyloxycarbonylamino)-3-(4-hydroxyphenyl)propionate as a solid;m.p. 119°-120° C.; NMR(d₆ DMSO.sub.): 1.34(s,9H), 2.54-2.78(m,2H),3.53(s,3H), 4.7-4.9(q,1H), 6.67(d,2H), 7.08(d,2H), 7.28(brd,1H),9.24(brs,1H).

(ii) Using a procedure similar to that described in Example 19, step(i), but using the product of step (i), methyl3-(t-butyloxycarbonylamino)-3- 4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!-propionate was prepared as agum; NMR(CDCl₃): 1.33-1.55(m,2H), 1.44(s,9H), 1.95(brd,2H),1.95-2.15(m,1H), 2.7-3.0(m,4H), 3.61(s,3H), 3.80(d,2H), 3.95(brd,2H),4.95-5.1(m,1H), 5.25-5.40(m,1H), 6.68(d,2H), 6.85(d,2H), 7.2(d,2H),8.25(d,2H).

(iii) The product of step (ii) (550 mg) and 5M methanolic hydrochloricacid solution (4 ml) was stirred at ambient temperature for 18 hours.The solvent was evaporated to give methyl 3-amino-3- 4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionate dihydrochloride asa foam; NMR(d₆ DMSO/CD₃ CO₂ D): 1.23-1.45(m,2H), 1.92(brd,2H),2.05-2.25(m,1H), 3.0-3.25(m,4H), 3.52(s, 3H) 3.85(d,2H), 4.2(brd,2H),4.54(t,1H), 6.92(d,2H), 7.1(d,2H), 7.39(d,2H), 8.10(d,2H).

EXAMPLE 62 3-(n-Butylsulphonylamino)-3- 4-1-(4-pyridyl)-piperidin-4-yl!methoxyphenyl!propionic acid.

Using a procedure similar to that described in Example 20, but using theproduct of Example 61, the title compound was prepared; NMR(d₆ DMSO/CD₃CO₂ D): 0.78(t,3H), 1.05-1.3(m,2H), 1.3-1.57(m,4H), 1.98(brd,2H),2.1-2.33(m,1H), 2.45-2.85(m,4H), 3.25(t,2H), 3.89(d,2H), 4.25(brd,2H),4.68(t,1H), 6.90(d,2H), 7.14(d,2H), 7.33(d,2H), 8.14(d,2H); massspectrum(+ve FAB,MeOH/NBA): 490(M+H)⁺.

EXAMPLE 63 Methyl 3-(4-methylphenylsulphonylamino)-3- 4-1-(4-pyridyl)-piperidin-4-yl!methoxyphenyl!propionate.

Using a procedure similar to that described in Example 19, but startingfrom the product of Example 61, step (iii) and p-toluenesulphonylchloride, the title compound was prepared; NMR(CDCl₃): 1.34-1.55(m,2H),1.95(d,2H), 2.0-2.2(m,1H), 2.38(s,3H), 2.62-3.05(m,4H), 3.55(s,3H),3.78(d,2H), 3.96(d,2H), 4.65(m,1H), 5.65(brs,1H), 6.7(d,2H), 6.72(d,2H),7.05(d,2H), 7.2(d,2H), 7.65(d,2H), 8.25(d,2H); mass spectrum(+veFAB,MeOH/NBA): 524(M+H)⁺.

EXAMPLE 64 Methyl 2-R-(n-butylsulphonylamino)-3- 4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionate.

Using a procedure similar to that described in Example 19, but startingfrom methyl 2-R-amino-3- 4-1-(4-pyridyl)piperidin-4-yl!-methoxyphenyl!propionate, the titlecompound was prepared; NMR(CDCl₃): 0.88(t,3H), 1.2-1.7(m,6H),1.96(d,2H), 2.0-2.2(m,1H), 2.7-2.83(m,2H), 2.85-3.15(m,4H), 3.77(s,3H),3.79(d,2H), 3.96(d,2H), 4.32(m,1H), 4.85(brd,1H), 6.7(d,2H), 6.83(d,2H),7.08(d,2H), 8.25(brd,2H); mass spectrum(+ve FAB,MeOH/NBA): 490(M+H)⁺.

The necessary starting material was prepared as follows:

(i) Using a similar procedure to that described in Example 19, step (i),but starting from N-t-butyloxycarbonyl-S-tyrosine methyl ester, therewas obtained, methyl 2-R-(t-butyloxycarbonylamino)-3- 4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!propionate as a gum,NMR(CDCl₃): 1.43(s,9H), 1.36-1.55(m,2H), 1.96(brd,2H), 2.0-2.15(m,1H),2.95(dt,2H), 3.03(d,2H), 3.71(s,3H), 3.81(d,2H), 3.95(brd,2H),4.52(brd,1H), 4.95(brd,1H), 6.70(d,2H), 6.80(d,2H), 7.01(d,2H),8.24(d,2H).

(ii) Using a similar procedure to that described in Example 59, step(ii), but starting from the product obtained in step (i), there wasobtained, methyl 2-R-amino-3- 4-1-(4-pyridyl)-piperidin-4-yl!methoxyphenyl!propionate dihydrochloride asa foam, NMR(d₆ DMSO/CD₃ CO₂ D): 1.26-1.48(m,2H), 1.96(brd,2H),2.1-2.3(m,1H), 3.09(dd,2H), 3.21(t,2H), 3.70(s,3H), 3.84(d,2H),4.15-4.3(m,3H), 6.88(d,2H), 7.14(m,4H), 8.14(d,2H).

EXAMPLE 65 2-R-(n-Butylsulphonylamino)-3- 4-1-(4-pyridyl)-piperidin-4-yl!-methoxyphenyl!propionic acid.

Following the method of Example 20, but using the product of Example 64,the title compound was prepared; NMR(d₆ DMSO): 0.75(t,3H),1.03-1.45(m,6H), 1.87(d,2H), 1.95-2.2(m,1H), 2.45-2.78(m,3H),2.88-3.08(m,3H), 3.82(d,2H), 3.8-3.95(m,1H), 4.05(brd,2H), 6.84(d,2H),6.92(d,2H), 7.18(d,2H), 8.13(brs,2H); mass spectrum(-ve FAB,MeOH/NBA):474(M-H)⁻ ; microanalysis found C,55.1; H,6.8; N,7.8%; C₂₄ H₃₃ N₃ O₅S.2.5H₂ O requires C,55.4; H,7.3; N,8.1%.

EXAMPLE 66 Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl-!2,6-dichlorophenoxyacetate.

Prepared in a similar manner to Example 5, but starting from methyl4-bromoacetyl-2,6-dichlorophenoxyacetate, however stirring for only 6hours and purification by flash chromatography on silica, eluting firstwith dichloromethane then successively 2,3,4 and 5% v/vmethanol/dichloromethane. Concentration of the fractions in vacuo andrecrystallisation of the residue from methanol gave the title compoundin 24% yield as a pale orange solid: m.p. 149°-150° C.;

NMR (d₆ DMSO) δ 8.14 (2H, d), 8.06 (2H, s), 6.81 (2H, d), 4.82 (2H, s),4.05 (0.5H, b), 3.94 (2H, s), 3.73 (3H, s), 3.32 (4H, t), 3.18 (1.5H,s), 2.64 (4H, t); m/e 438 (M+H)⁺, 2×Cl pattern; calculated for C₂₀ H₂₁Cl₂ N₃ O₄.0.5CH₃ OH: C, 54.1; H, 5.1; N, 9.2. found: C, 53.7; H, 5.4; N,8.9%.

The starting material was prepared as follows:

(i) Sodium hydride (50% w/w dispersion in mineral oil, 1.32 g) wastreated under argon with repeated washes of hexane. The oil-free residuewas suspended in dry DMF (10 ml) and, with stirring and cooling(ice-bath), a solution of 3,5-dichloro-4-hydroxyacetophenone (5.13 g) indry DMF (15 ml) was added dropwise. Stirring was continued for 30minutes when methyl bromoacetate (3.06 ml) was added dropwise andstirring was continued for a further 18 hours at ambient temperature.The reaction mixture was added to water, the mixture was extracted twicewith ethyl acetate, the organic phases dried (MgSO₄), filtered and thenevaporated. The residue, after recrystallisation from hexane (250 ml),gave methyl 4-acetyl-2,6-dichlorophenoxyacetate, 4.25 g, as whitecrystals: NMR (d₆ DMSO) δ 8.00 (2H, s), 4.80 (2H, s), 3.73 (3H, s), 2.59(3H, s).

(ii) A solution of bromine (0.77 ml) in chloroform (10 ml) was addeddropwise over 15 minutes to a stirred solution of the product from step(i) (4.16 g) in chloroform (40 ml) at 25° C. The temperature was raisedto 40° C. for 1 hour and then stirring continued for a further 18 hoursat ambient temperature. The solvent was removed in vacuo and theresidual oil purified by flash chromatography on silica, eluting withdichloromethane, to give a crystalline solid. Recrystallisation frommethanol gave methyl 4-bromoacetyl-2,5-dichlorophenoxyacetate, 1.88 g,as white crystals: m.p. 89°-90° C.; NMR (d₆ DMSO) δ 8.06 (2H, s), 4.93(2H, s), 4.82 (2H, s), 3.72 (3H, s); m/e 355/357 (M+H)⁺, 1 Br pattern;calculated for C₁₁ H₉ BrCl₂ O₄ : C, 37.1; H, 2.3. found: C, 36.8; H,2.4%.

EXAMPLE 67 Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-3-methylphenoxyacetate.

In a similar manner to Example 5, but starting from methyl4-bromoacetyl-3-methylphenoxyacetate and with purification by flashchromatography on silica, eluting with 0 to 5% v/vmethanol/dichloromethane, and then by flash chromatography on neutralalumina, eluting first with dichloromethane and then 1% v/vmethanol/dichloromethane there was obtained the title compound in 9%yield as a yellow oil: NMR (d₆ DMSO) δ 8.15 (2H, d), 7.38 (1H, d), 6.82(4H, m), 4.88 (2H, s), 3.75 (2H, s), 3.71 (3H, s), 3.32 (4H, t), 2.61(4H, t), 2.43 (3H, s), m/e 384 (M+H)⁺ ; calculated for C₂₁ H₂₅ N₃O₄.0.5H₂ O.0.1 CH₂ Cl₂ : C, 63.1; H, 6.5; N, 10.5. found: C, 62.6; H,6.6; N, 10.2%.

The starting material was prepared as follows:

(i) A mixture of 4-hydroxy-2-methylacetophenone (4.8 g), anhydrouspotassium carbonate (5.3 g) and methyl bromoacetate (3.55 ml) inanhydrous acetone (100 ml) was stirred for 2 days. The mixture, afterfiltration and evaporation of the solvent, gave methyl4-acetyl-3-methylphenoxyacetate, 6.6 g, as a crystalline solid: m.p.49°-50° C.; NMR (d₆ DMSO) δ 7.84 (1H, d), 6.83 (2H, m), 4.87 (2H, s),3.71 (3H, s), 2.50 (3H, s), 2.45 (3H, s).

(ii) Prepared in a similar manner to Example 76 step (ii), but startingfrom the product of (i) above and purification by flash chromatographyon silica eluting with 10 to 17.5% v/v ethyl acetate/hexane.Recrystallisation from ethanol gave methyl4-bromoacetyl-3-methylphenoxyacetate, in 35% yield, as white needles:NMR (d₆ DMSO) δ 7.90 (1H, d), 6.90 (1H, s), 6.88 (1H, d), 4.90 (2H, s),4.78 (2H, s), 3.71 (3H, s), 2.43 (3H, s).

EXAMPLE 68 Mixture of methyl 4- 2-4-(4-pyridyl)piperazin-1-yl)-acetyl!-2-methylphenoxyacetate and ethyl 4-2- 4-(4-pyridyl)piperazin-1-yl!acetyl!-2-methylphenoxyacetate (3:2).

A mixture of methyl 4-acetyl-2-methylphenoxyacetate (3.33 g) and cupricbromide (7.0 g) in ethyl acetate (50 ml) was heated on a steam bath for18 hours. After filtration, the solvent was evaporated and the residualsolid purified by flash chromatography on silica eluting with 10% v/vethyl acetate/hexane to give an off-white solid. Recrystallisation fromethanol gave white needles, 2.37 g, shown by NMR (d₆ DMSO) to be amixture of methyl 4-bromoacetyl-2-methylphenoxyacetate and ethyl4-bromoacetyl-2-methylphenoxyacetate which was used without furtherpurification. The mixture (2.25 g) was added portionwise to a stirredsolution of 1-(4-pyridyl)piperazine (2.45 g) in acetonitrile (50 ml) andthe mixture stirred for 18 hours. The reaction mixture was filtered andthe filtrate evaporated to give an orange oil. Purification by flashchromatography on silica eluting with dichloromethane then 1 to 3% v/vmethanol/dichloromethane gave the title mixture of compounds, 0.87 g, asa solid: m.p. 136°-138° C.; NMR (d₆ DMSO) δ 8.04 (2H, d), 7.85 (1H, d),7.82 (1H, s), 6.95 (1H, d), 6.81 (2H, d), 4.96 and 4.93 (2H, s,s), 4.18(0.7H, q), 3.84 (2H, s), 3.72 (1.7H, s), 3.30 (4H, t), 2.60 (4H, t),2.25 (3H, s), 1.21 (1.3H, t), Ratio of methyl to ethyl ester 3:2!; m/e384 (M+H)⁺ for methyl ester, 398 (M+H)⁺ for ethyl ester; calculated forC₂₁ H₂₅ N₃ O₄ : C₂₂ H₂₇ N₃ O₄ (3:2): C, 66.1; H, 6.6; N, 10.8. found: C,65.8; H, 6.7; N, 10.5%.

The starting material was prepared as follows:

(i) A mixture of 4-hydroxy-3-methylacetophenone (5 g), methylbromoacetate (3.70 ml) and anhydrous potassium carbonate (5.52 g) inacetone (100 ml) was stirred for 66 hours. The mixture was filtered andthe filtrate evaporated to give an oil which crystallised on standinggiving methyl 4-acetyl-2-methylphenoxyacetate, 7.2 g: m.p. 51°-53° C.;NMR (d₆ DMSO) δ 7.79 (1H, s), 7.77 (1H, d), 6.94(1H,d), 4.93 (2H, s),3.71 (3H, s), 2.50 (3H, s+DMSO), 2.24 (3H, s).

EXAMPLE 69 Mixture of methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!-acetyl!-3-methoxyphenoxyacetate and ethyl4-2- 4-(4-pyridyl)piperazin-1-yl!acetyl!-3-methoxyphenoxyacetate (3:1).

In a similar manner to Example 68, but starting from methyl4-acetyl-3-methoxyphenoxyacetate there was prepared, after flashchromatography on silica eluting with dichloromethane, a mixture ofmethyl 4-bromoacetyl-3-methoxyphenoxyacetate and ethyl4-bromoacetyl-3-methoxyphenoxyacetate in 60% yield: m.p. 84°-86° C.Treatment of this mixture, as in Example 68, followed by chromatographyon silica eluting with 1 to 5% v/v methanol/dichloromethane gave thetitle mixture of compounds in 24% yield as a solid: NMR (d₆ DMSO) δ 8.13(2H, d), 7.63 (1H, d), 6.80 (2H, d), 6.67 (1H, d), 6.59 (1H, dd), 4.90and 4.88 (2H, 2s), 4.18 (0.5, q), 3.88 (3H, s), 3.75 (2H, s), 3.71(2.3H, s), 3.32 (4H, t), 2.62 (4H, t), 1.22 (0.7 H, t) Ratio of methylto ethyl ester 3:1!; m/e 400 (M+H)⁺ for methyl ester, 414 (M+H)⁺ forethyl ester; calculated for C₂₁ H₂₅ N₃ O₅ : C₂₂ H₂₇ N₃ O₅ (3:1): C,63.3; H, 6.5; N, 10.4. found C, 63.1; H, 6.5; N, 10.3%.

The starting material was prepared as follows:

(i) In a similar manner to Example 68 step (i), but starting from4-hydroxy-2-methoxy-acetophenone there was obtained, after evaporationof the solvent and trituration with diethyl ether, methyl4-acetyl-3-methoxyphenoxyacetate in 91% yield as a white solid: m.p.95°-96° C.; NMR (d₆ DMSO) δ 7.64 (1H, d), 6.70 (1H, d), 6.60 (1H, dd),4.91 (2H, s), 3.89 (3H, s), 3.72 (3H, s), 2.49 (3H, s).

EXAMPLE 70 Mixture of dimethyl 2,2'- 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenylene-1,3-dioxy!diacetate anddiethyl 2,2'- 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenylene-1,3-dioxy!-diacetate(1:1).

In a similar manner to Example 68, but starting from dimethyl 2,2'-(4-acetyl)phenylene-1,3-dioxy!diacetate there was prepared, after flashchromatography on silica eluting with dichloromethane, a mixture ofdimethyl 2,2'- (4-bromoacetyl)phenylene-1,3-dioxy!diacetate and diethyl2,2'- (4-bromoacetyl)phenylene-1,3-dioxy!diacetate in 28% yield.Treatment of the mixture, as in Example 68, followed by chromatographyon silica eluting with 1 to 5% v/v methanol/dichloromethane gave thetitle mixture of compounds in 44% yield as a solid: NMR (d₆ DMSO) δ 8.14(2H, d), 7.63 (1H, d), 6.82 (2H, d), 6.65 (2H, d), 4.96 and 4.93 (2H,2s), 4.49 and 4.47 (2H, 2s), 4.20 (2H, m), 3.91 (2H, s), 3.75 and 3.71(3H, 2s), 3.32 (4H+H₂ O), 2.61 (4H, t), 1.23 (3H, m) Ratio of methyl toethyl esters 1:1!; m/e 458 (M+H)⁺ for dimethyl ester and 486 (M+H)⁺ fordiethyl ester; calculated for C₂₃ H₂₇ N₃ O₇ :C₂₅ H₃₁ N₃ O₇ (1:1). H₂O:C,60.0; H, 6.3; N, 8.7. found: C, 60.3; H, 6.2; N, 8.5%.

The starting material was prepared as follows:.

(i) In a similar manner to Example 68 step (i), but starting from2,4-dihydroxy-acetophenone and using 2.4 equivalents of methylbromoacetate and 2.4 equivalents of anhydrous potassium carbonate therewas obtained, after evaporation and trituration with diethylether/hexane (1:1 v/v), dimethyl 2,2'-(4-acetyl)phenylene-1,3-dioxy!diacetate in 82% yield as a white solid:m.p. 119°-120° C.; NMR (d₆ DMSO) δ 7.64 (1H, d), 6.56 (2H, m), 4.99 (2H,s), 4.90 (2H, s), 3.73 (3H, s), 3.71 (3H, s), 2.57 (3H, s).

EXAMPLE 71 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-2,6-dichlorophenoxyacetic acid,dihydrochloride.

A solution of the product of Example 66 (190 mg) in dioxane (1.7 ml) wastreated with 1N hydrochloric acid (1.7 ml) and the mixture heated at100° C. for 1.5 hours. The mixture was cooled, diluted with water andfreeze-dried. The solid residue, on treatment with a small volume ofethanol, gave the title compound, 120 mg, as a white solid: m.p.174°-176° C.; NMR (D₂ O) δ 8.42 (2H, d), 8.26 (2H, s), 7.41 (2H, d),5.24 (2H, s), 4.98 (2H, s), 4.34 (4H, t), 3.90 (4H, t); m/e 424 (M+H)⁺,2×Cl pattern; calculated for C₁₉ H₁₉ Cl₂ N₃ O₄.2HCl. H₂ O: C, 44.4; H,4.5; N, 8.2. found: C, 44.8; H, 4.2; N, 8.1%.

EXAMPLES 72 to 75

In a similar manner to Example 71, but starting from the product ofExamples 63 to 66 the following compounds were prepared:

EXAMPLE 72 4- 2- 4-(4-Pyridyl)piperazin-1-ylacetyl)-3-methylphenoxyacetic acid, dihydrochloride.

The title compound was prepared from the product of Example 67 in 78%yield: m.p. 242°-244° C.; NMR (D₂ O) δ 8.38 (2H, d), 8.00 (1H, d), 7.36(2H, d), 7.14 (1H, s), 7.10 (1H, d), 5.12 (2H, s), 4.97 (2H, s), 4.30(4H, bs), 3.84 (4H, bs), 2.75 (3H, s); m/e 370 (M+H)⁺ ; calculated forC₂₀ H₂₃ N₃ O₄. 2HCl. 0.5H₂ O: C, 53.4; H, 5.3; N, 9.3. found C, 53.2; H,5.8; N, 8.8%.

EXAMPLE 73 4- 2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-2-methyl-phenoxyacetic acid,dihydrochloride.

The title compound was prepared from the product of Example 68 in 98%yield: m.p. 259° to 263° C.; NMR (d₆ DMSO+D₂ O) δ 8.46 (2H, d), 7.95(2H, m), 7.38 (2H, d), 7.15 (1H, d), 5.17 (2H, s), 5.00 (2H, s), 4.19(4H, s), 3.62 (4H, s), 2.39 (3H, s); m/e 370 (M+H)⁺ ; calculated for C₂₀H₂₃ N₃ O₄.2HCl. 0.5H₂ O: C, 53.5; H, 5.8; N, 9.4. found: C, 53.6; H,5.7; N, 9.5%.

EXAMPLE 74 4- 2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-3-methoxy-phenoxyacetic acid,dihydrochloride.

The title compound was prepared from the product of Example 69 in 69%yield: m.p. 168°-170° C.; NMR (d₆ DMSO+d₄ acetic acid) δ 8.36 (2H, d),7.93 (1H, d), 7.28 (2H, d), 6.76 (1H, d), 6.72 (1H, dd), 4.86 (2H, s),4.78 (2H, s), 4.08 (4H, bs), 3.98 (3H, s), 3.54 (4H, bs); m/e 386 (M+H)⁺; calculated for C₂₀ H₂₃ N₃ O₅.2HCl.2H₂ O: C, 48.7; H, 5.9; N, 8.5.found: C, 48.5; H, 5.7; N, 8.3%.

EXAMPLE 75 2,2'- 4- 2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-phenylene-1,3-dioxy!diacetic acid,dihydrochloride.

The title compound was prepared from the product of Example 70 in 79%yield: m.p. 257°-258° C.; NMR (D₂ O) δ 8.39 (2H, d), 8.18 (1H, d), 7.48(2H, d), 6.94 (1H, dd), 6.76 (1H, d), 5.18 (2H, s), 5.09 (2H, s), 5.01(2H, s), 4.29 (4H, b), 3.34 (4H, b); m/e 430 (M+H)⁺ ; calculated for C₂₁H₂₄ N₃ O₇.2HCl.0.5H₂ O: C, 49.5; H, 5.3; N, 8.2. found C, 49.4; H, 5.3;N, 7.8%.

EXAMPLE 76 4-2-4-(4-Pyridyl)piperazin-1-yl!acetyl!-2,6-di-tert-butylphenoxyaceticacid.

A solution of methyl 4-(2-4-(4-pyridyl)piperazin-1-yl!-acetyl)-2,6-di-tert-butylphenoxyacetate(241 mg) in dioxane (2.0 ml) was treated with 1N hydrochloric acid andthe mixture heated at 100° C. for 20 hours. The mixture was cooled,diluted with water, filtered and the filtrate freeze-dried. The solidresidue was purified by flash chromatography on silica eluting withtoluene/ethyl acetate/0.880 ammonia/ethanol (60:20:10:35 v/v/v/v). Thefractions containing the desired product were evaporated, the residuetreated with dioxane, filtered and the filtrate diluted with water andfreeze dried to give a white foam, which on drying at 55° C. gave thetitle compound, 90 mg: NMR (d₆ DMSO) δ 8.16 (2H, d), 7.97 (2H, s), 6.84(2H, d), 4.22 (2H, s), 3.86 (2H, s), 3.37 (4H, t), 2.64 (4H, t), 1.39(18H, s); m/e 468 (M+H)⁺ ; calculated for C₂₇ H₃₇ N₃ O₄.2H₂ O: C, 64.4;H, 8.2; N, 8.3. found C, 64.6; H, 7.9; N, 7.9%.

The starting material was prepared as follows:

(i) In a similar manner to Example 66 step (i), but starting from2,5-di-tert-butyl-4-hydroxyacetophenone there was obtained from theethyl acetate extracts a brown oil. Flash chromatography on silica,eluting with successively hexane, then 2% v/v ethyl acetate/hexane andfinally 5% v/v ethyl acetate/hexane gave methyl4-acetyl-2,6-di-tert-butylphenoxyacetate in 50% yield as an oil: NMR (d₆DMSO) δ 7.84 (2H, s), 4.38 (2H, s), 3.76 (3H, s), 2.55 (3H, s), 1.40(18H, s); m/e 321 (M+H)⁺ ; calculated for C₁₉ H₂₈ O₄ : C, 71.2; H, 8.8.found C, 71.5; H, 9.0%.

(ii) A mixture of the product from step (i) above (4.91 g) and cupricbromide (6.82 g) in ethyl acetate (45 ml) was heated at refluxtemperature for 24 hours. On cooling, the mixture was filtered and thefiltrate concentrated in vacuo. The residue on purification by flashchromatography on silica, eluting with 5% v/v ethyl acetate/hexane, gavemethyl 4-bromoacetyl-2,6-di-tert-butylphenoxy-acetate, 4.98 g, as anoil: NMR (d₆ DMSO) δ 7.90 (2H, s), 4.92 (2H, s), 4.40 (2H, s), 3.76 (3H,s), 1.41 (18H, s).

(iii) In a similar manner to Example 5, but starting from the product ofstep (ii) above and with purification by flash chromatography on silicaeluting successively with dichloromethane then 2 to 5% v/vmethanol/dichloromethane there was obtained a solid. Trituration withether gave methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-2,6-di-tert-butylphenoxyacetate in33% yield: m.p. 140°-142° C.; NMR (d₆ DMSO) δ7.97 (2H, s), 6.82 (2H, d),4.39 (2H, s), 3.85 (2H, s), 3.75 (3H, s), 3.33 (4H, t), 2.64 (4H, t),1.39 (18H, s); m/e 482 (M+H)⁺ ; calculated for C₂₈ H₃₉ N₃ O₄ : C, 69.8;H, 8.2; N, 8.7. found: C, 69.7; H, 8.6; N, 8.1%.

EXAMPLE 77 Ethyl 4- 2- 4-(4-pyridyl)piperazin-1-yl!acetyl!benzoate

Prepared in a similar manner to Example 5, but starting from ethyl4-bromoacetylbenzoate; recrystallisation from methanol gave the titlecompound in 32% yield as pale yellow crystals: m.p. 147°-149° C.; NMR(d₆ DMSO) δ 8.14 (2H, d), 8.08 (4H, q), 6.78 (2H, d), 4.35 (4H, q, ABpattern), 3.98 (2H, s), 3.31 (4H, t), 2.63 (4H, t), 1.35 (3H, t); m/e354 (M+H)⁺ ; calculated for C₂₀ H₂₃ N₃ O₃ : C, 68.0; H, 6.6; N, 11.9.found: C, 68.0; H, 6.5; N, 11.7%.

EXAMPLE 78 Sodium 4- 2- 4-(4-pyridyl)piperazin-1-yl!acetyl!benzoate.

A stirred suspension of the product of Example 77 (353 mg) in methanol(5 ml) was treated with a 1 molar sodium hydroxide solution (3 ml).After 2 hours, the cream coloured solid was collected, washed with alittle methanol and dried to give the title compound, 240 mg, m.p.>300°C.; NMR (d₆ DMSO) δ 8.15 (2H, d), 8.05 (4H, t, AB pattern), 6.85 (2H,d), 3.97 (2H, s), 3.38 (4H, t), 2.65 (4H, t), m/e 348 (M+H)⁺ ;calculated for C₁₈ H₁₈ N₃ NaO₃. 0.25H₂ O: C, 61.4; H, 5.3; N, 11.9.found: C, 61.3; H, 5.2; N, 11.7%.

EXAMPLE 79 2- 4- 2-2-(4-pyridyl)piperazin-1-yl!acetyl!phenoxy!-isobutyric acid,dihydrobromide.

A mixture of methyl 2- 4- 2-4-(4-pyridyl)piperazin-1-yl!-acetyl!phenoxy!isobutyrate (50 mg), 48% w/vhydrobromic acid (0.74 ml), dioxane (1 ml) and water (3 ml) was heatedat 95° C. for 4 hours. The solution was cooled, diluted with water andfreeze-dried to give the title compound, 40 mg, as a pale yellow solid:m.p. 163°-167° C.; NMR (D₂ O) δ 8.40 (2H, d), 8.16 (2H, d), 7.40 (2H,d), 7.21 (2H, d), 5.21 (2H, s), 4.32 (4H, b), 3.89 (4H, bt), 1.86 (6H,s); m/e 384 (M+H)⁺ ; calculated for C₂₁ H₂₅ N₃.2HBr.2H₂ O: C, 43.3; H,5.3; N, 7.2. found: C, 43.6; H, 5.3; N, 7.3%.

The starting material was prepared as follows:

(i) In a similar manner to Example 66 step (ii) but starting from methyl2-(4-acetylphenoxy)isobutyrate and purification by flash chromatographyon silica, eluting with ethyl acetate/hexane (1:2 v/v), there wasobtained methyl 2-(4-bromoacetylphenoxy)isobutyrate in 45% yield as anorange oil: NMR (CDCl₃) δ 7.91 (2H, d), 6.85 (2H, d), 4.48 (2H, s), 3.76(3H, s), 1.67 (6H, s). m/e 315/317 (M+H)⁺ 2 Br pattern.

(ii) The product from step (i) above (2.00 g) in acetonitrile (10 ml)was added dropwise over 15 minutes to a stirred solution of1-(4-pyridyl)piperazine (1.04 g) and triethylamine (0.89 ml) inacetonitrile (15 ml) and the mixture stirred overnight. The precipitatedsolid was removed by filtration and the filtrate evaporated.Purification of the residue by flash chromatography on silica, elutingwith 0 to 5% v/v methanol/dichloromethane, gave a yellow gum.Trituration of this gum with diethyl ether gave methyl 2- 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!phenoxy!isobutyrate, 170 mg, as awhite solid: m.p. 88°-90° C.; NMR (d₆ DMSO) δ 8.15 (2H, d), 7.96 (2H,d), 6.82 (4H, m), 3.92 (2H, s), 3.70 (3H, s), 3.33 (4H, t), 2.63 (4H,t), 1.60 (6H, s); m/e 398 (M+H)⁺ ; calculated for C₂₂ H₂₇ N₃ O₄.0.25H₂O: C, 65.8; H, 6.8; N, 10.5. found: C, 65.8; H, 7.1; N, 10.4%.

EXAMPLE 80 Ethyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenoxyacetate.

Ethyl 4-bromoacetylphenoxyacetate (6.0 g) was added to a stirred, cooled(4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile (225ml). Stirring was continued for 1 hour at 4° C., then overnight atambient temperature when the precipitated solid was removed byfiltration. The filtrate was evaporated in vacuo and the solid residuetriturated with water, filtered, then washed with water and dried.Recrystallisation from a small volume of ethanol gave the titlecompound, 1.71 g, as a cream coloured solid: m.p. 113°-114° C.; NMR (d₆DMSO) δ 8.15 (2H, d), 7.98 (2H, d), 7.02 (2H, d), 6.80 (2H, d), 4.89(2H, d), 4.17 (2H, q), 3.84 (2H, s), 3.32 (4H, t), 2.62 (4H, t), 1.22(3H, t); m/e 384 (M+H)⁺ ; calculated for C₂₁ H₂₅ N₃ O₄ : C, 65.8; H,6.6; N, 11.0. found: C, 65.5; H, 6.6; N, 10.8%.

The starting material was prepared as follows:

(i) In a similar manner to Example 67 step (i), but starting from ethylbromoacetate there was prepared ethyl 4-acetylphenoxyacetate as acrystalline solid in quantitative yield. The product was used withoutfurther purification.

(ii) In a similar manner to Example 76 step (ii), but starting from theproduct of step (i) above there was prepared ethyl4-bromoacetylphenoxyacetate in 47% yield as a solid: m.p. 41°-42° C.;NMR (d₆ DMSO) δ 7.90 (2H, d), 7.05 (2H, d), 4.90 (2H, s), 4.72 (2H, s),4.18 (2H, q), 1.33 (3H, t).

EXAMPLE 81 iso-Propyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenoxyacetate.

iso-Propyl 4-bromoacetylphenoxyacetate (6.3 g) was added to a stirred,cooled (4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) inacetonitrile (225 ml). Stirring was continued for 1 hour at 4° C., thenovernight at ambient temperature when the precipitated solid wasremoved. The filtrate was evaporated in vacuo and the residuepartitioned between ethyl acetate and water. The organic phase was dried(MgSO₄) and evaporated. Purification by flash chromatography on silica,eluting firstly with 0 to 10% v/v methanol/dichloromethane and thentoluene/ethyl acetate/.880 ammonium hydroxide/ethanol (60:20:10:35v/v/v/v), gave a cream solid. Recrystallisation from iso-propanol gavethe title compound, 2.1 g: m.p. 121°-122° C.; NMR (d₆ DMSO) δ 8.14 (2H,d), 7.98 (2H, d), 7.02 (2H, d), 6.80 (2H, d), 4.99 (1H, m), 4.85 (2H,s), 3.84 (2H, s), 3.33 (4H, t), 2.62 (4H, t), 1.22 (6H, d); m/e 398(M+H)⁺ ; calculated for C₂₂ H₂₇ N₃ O₄ : C, 66.5; H, 6.9; N, 10.6. found:C, 65.8; H, 6.8; N, 10.4%.

The starting material was prepared as follows:

(i) In a similar manner to Example 67 step (i), but starting fromiso-propyl bromoacetate there was prepared iso-propyl4-acetylphenoxyacetate as a crystalline solid in quantitative yield. Theproduct was used without further purification.

(ii) In a manner similar to Example 76 step (ii), but starting from theproduct of step (i) above and using iso-propyl acetate in place of ethylacetate as solvent, there was prepared iso-propyl4-bromoacetylphenoxyacetate as a crystalline solid in 69% yield: m.p.64°-66° C.; NMR (d₆ DMSO) δ 7.98 (2H, d), 7.06 (2H, d), 4.99 (1H, m),4.88 (2H, s), 4.83 (2H, s), 1.22 (6H, d).

EXAMPLE 82 tert-Butyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenoxyacetate.

Prepared in a similar manner to Example 80, but starting from tert-butyl4-bromoacetylphenoxyacetate. After evaporation of the acetonitrilesolution the residue was purified by column chromatography on silica,eluting with 0 to 5% v/v methanol/dichloromethane, to give a yellow oil.Trituration with diethyl ether gave the title compound in 35% yield as asolid: m.p. 103°-104° C.; NMR (d₆ DMSO) δ 8.15 (2H, d), 7.98 (2H, d),7.00 (2H, d), 6.82 (2H, d), 4.76 (2H, s), 3.84 (2H, s), 3.37 (4H, t),2.62 (4H, t), 1.43 (9H, s); m/e 412 (M+H)⁺ calculated for C₂₃ H₂₉ N₃ O₄: C, 67.1; H, 7.1; N, 10.2. found: C, 66.9; 7.3; N, 10.0%.

The starting material was prepared as follows:

(i) In a similar manner to Example 67 step (i), but starting fromtert-butyl bromoacetate there was prepared tert-butyl4-acetylphenoxyacetate as a crystalline solid in 90% yield: m.p. 59°-61°C.; NMR (d₆ DMSO+d₄ acetic acid) δ 7.94 (2H, d), 6.98 (2H, d), 4.21 (2H,s), 2.52 (3H, s), 1.44 (9H, s).

(ii) A solution of the product from step (i) above (3.3 g) andN-bromosuccinimide (2.35 g) in carbon tetrachloride was heated at refluxtemperature for 80 hours. After cooling, the precipitate was removed byfiltration and the filtrate concentrated in vacuo. Purification of theresidual oil by flash chromatography on silica, eluting with 5% v/vethyl acetate/toluene, gave tert-butyl 4-bromoacetylphenoxyacetate, 1.9g, as a crystalline solid: m.p. softens at 110°-116° C.; NMR (d₆ DMSO) δ7.97 (2H, d), 7.04 (2H, d), 4.84 (2H, s), 4.80 (2H, s), 1.43 (9H, s).

EXAMPLE 83 Neopentyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenoxyacetate.

Prepared in a similar manner to Example 80, but starting from neopentyl4-bromoacetylphenoxyacetate. After evaporation of the acetonitrilefiltrate, the residue was purified by flash chromatography on silica,eluting with 0 to 5% v/v methanol dichloromethane, to give an oil.Trituration with diethyl ether/hexane gave the title compound in 23%yield as a solid: m.p. 88°-90° C.; NMR (d₆ DMSO) δ 8.14 (2H, d), 7.98(2H, d), 7.04 (2H, d), 6.81 (2H, d), 4.97 (2H, s), 3.83 (4H, s), 3.32(4H, t), 2.61 (4H, t), 0.86 (9H, s); m/e 426 (M+H)⁺ ; calculated for C₂₄H₃₁ N₃ O₄ : C, 67.7; H, 7.3; N, 9.9. found: C, 68.1; H, 7.4; N, 9.9%.

The starting material was prepared as follows:

To a stirred suspension of 4-acetylphenoxyacetic acid (4.36 g) indichloromethane (50 ml) was added oxalyl chloride (2.36 ml) and DMF (onedrop). The mixture was stirred for one hour and then the solvent removedin vacuo to give a yellow oil (4.8 g). A solution of this oil in diethylether was added dropwise to a stirred solution of neopentyl alcohol(2.18 g) and triethylamine (3.4 ml) in diethyl ether (50 ml). After theaddition, stirring was continued for a further 18 hours when theprecipitated solid was removed by filtration. Evaporation of thefiltrate and purification of the residue by flash chromatography onsilica, eluting with dichloromethane, gave neopentyl4-acetylphenoxyacetate, 5.1 g, as a pale yellow oil: NMR (CDCl₃) δ 7.94(2H, d), 6.95 (2H, d), 4.72 (2H, s), 3.91 (2H, s), 2.56 (3H, s), 0.93(9H, s).

(ii) To a stirred solution of the product of step (i) above (2.64 g) inchloroform (25 ml), was added slowly over 10 minutes, a solution ofbromine (0.52 ml) in chloroform (10 ml). Stirring was continued for afurther hour and the solvent removed in vacuo. Trituration of theresidue with diethyl ether/hexane gave neopentyl4-bromoacetylphenoxyacetate, 2.3 g, as a crystalline solid: m.p. 85°-87°C.

EXAMPLE 84 Dimethyl 4- 2-4-(4-pyridyl)piperazin-1-yl!acetyl!-phenoxymalonate.

Prepared in a similar manner to Example 80, but starting from dimethyl4-bromoacetylphenoxymalonate and after evaporation of the acetonitrilefiltrate the residue was partitioned between water/dichloromethane. Theorganic solution was dried (MgSO₄), concentrated and purification byflash chromatography, eluting with 0 to 5% v/v methanol/dichloromethane,then trituration with diethyl ether gave the title compound in 31% yieldas a pale yellow solid: m.p. 115°-116° C.;

NMR (d₆ DMSO) δ 8.16 (2H, d), 8.02 (2H, d), 7.09 (2H, d), 6.82 (2H, d),5.95 (1H, s), 3.86 (2H, s), 3.80 (6H, s), 3.34 (4H, t), 2.63 (4H, t);m/e 428 (M+H)⁺ ; calculated for C₂₂ H₂₅ N₃ O₆ : C, 61.8; H, 5.9; N, 9.8.found C, 61.3; H, 5.9; N, 9.2%.

The starting material was prepared as follows:

(i) In a similar manner to Example 67 step (i), but starting fromdimethyl bromomalonate and purification by flash chromatography onsilica, eluting with 50 to 75% v/v diethyl ether/hexane, there wasprepared dimethyl 4-acetylphenoxymalonate in 53% yield as a whitecrystalline solid: m.p. 71°-72° C.; NMR (d₆ DMSO) δ 7.95 (2H, d), 7.09(2H, d) 5.95 (1H, s) 3.78 (6H, s) 2.53 (3H s); m/e 267 (M+H)⁺ ;calculated for C₁₃ H₁₄ O₆ : C, 58.6; H, 5.3. found: C, 58.9; H, 5.3%.

(ii) In a similar manner to Example 76 step (ii), but starting from theproduct of step (i) above and using methyl acetate in place of ethylacetate as solvent, there was prepared methyl4-bromoacetylphenoxymalonate in 59% yield as a white crystalline solid:m.p. 114°-115° C.; NMR (d₆ DMSO) δ 7.99 (2H, d), 7.12 (2H, d), 5.99 (1H,s), 4.86 (2H, s), 3.80 (6H, s).

EXAMPLE 85 4- 2- 4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxy-acetamide

A solution of the product of Example 1 (200 mg) in methanol (10 ml),prepared under argon, was cooled to 4° C. and saturated with dry ammoniagas, then sealed in a pressure bottle and kept for 2 days. The orangecrystals which formed, after filtration and washing with a littlemethanol, gave the title compound, 140 mg: m.p. 247° to 248° C.; NMR (d₆DMSO) δ 8.16 (2H, d), 7.99 (2H, d), 7.55 (1H, bs), 7.37 (1H, bs), 7.02(2H, d), 6.81 (2H, d), 4.54 (2H, s), 3.85 (2H, s), 3.33 (4H, t), 2.60(4H, t); m/e 355 (M+H)⁺ ; calculated for C₁₉ H₂₂ N₄ O₃ : C, 64.4; H,6.3; N, 15.8. found: C, 64.4; H, 6.4; N, 15.6%.

EXAMPLE 86 2- 4- 2-4-(4-Pyridyl)piperazin-1-yl!acetyl!phenoxy!-N-methylacetamide.

A suspension of the product of Example 1 (100 mg) in a 33% w/v solutionof methylamine in ethanol (3 ml) was stirred for 18 hours. The solidformed, after filtration and washing with a little ethyl acetate, gavethe title compound, 65 mg: m.p. 169°-171° C.; NMR (d₆ DMSO) δ 8.14 (2H,d), 8.06 (1H, bq), 8.00 (2H, d), 7.05 (2H, d), 6.80 (2H, d), 4.56 (2H,s), 3.82 (2H, s), 3.30 (4H, t), 2.66 (3H, d), 2.61 (4H, t); m/e 369(M+H)⁺ ; calculated for C₂₀ H₂₄ N₄ O₃ : C, 65.2; H, 6.6; N, 15.2. found:C, 65.0; H, 6.8; N, 15.1%.

EXAMPLE 87 2- 4- 2-4-(4Pyridyl)piperazin-1-yl!acetyl!phenoxy!-N-(2-methoxyethyl)acetamide.

A suspension of the product of Example 1, (100 mg) in2-methoxyethylamine (1 ml) was stirred for 18 hours. Filtration of thesolid and washing with ethyl acetate gave the title compound, 70 mg, asa white crystalline solid: m.p. 142°-145° C.; NMR (d₆ DMSO+d₄ aceticacid) δ 8.20 (2H, d), 8.00 (2H, d), 7.14 (2H, d), 7.06 (2H, d), 4.62(2H, s), 3.72 (4H, t), 3.38 (4H, m), 3.26 (3H, s), 2.78 (4H, t); m/e 413(M+H)⁺ ; calculated for C₂₂ H₂₈ N₄ O₄ : C, 64.1; H, 6.8; N, 13.6. found:C, 63.9; H, 6.8; N, 13.3%.

EXAMPLE 88 2- 4- 2-(4-(4-Pyridyl)piperazin-1-ylacetyl!phenoxy!-N-(phenylmethyl)acetamide.

A solution of 2- 4-(bromoacetyl)phenoxy!-N-(phenylmethyl)acetamide (1.40g) (preparation described in EPO 052442) in acetonitrile (5 ml) wasadded to a stirred solution of 1-(4-pyridyl)piperazine (1.14 g) inacetonitrile (20 ml). After stirring overnight the liquors were decantedfrom the residual gum, then concentrated in vacuo. Purification by flashchromatography on silica, eluting with 2 to 5% v/vmethanol/dichloromethane, gave a solid. Trituration of this solid withdiethyl ether gave the title compound, 95 mg: m.p. 150°-151° C.; NMR (d₆DMSO) δ 8.67 (1H, bt), 8.15 (2H, d), 8.00 (2H, d), 7.26 (5H, m), 7.06(2H, d), 6.81 (2H, d), 4.66 (2H, s), 4.34 (2H, d), 3.84 (2H, s), 3.33(4H, t), 2.54 (4H, t); m/e 445 (M+H)⁺ ; calculated for C₂₆ H₂₈ N₄ O₃.0.25H₂ O: C, 69.5; H, 6.4; 12.5. found: C, 69.6; H, 6.4; N, 12.3%.

EXAMPLE 89 Methyl N- 4- 2-4-(4-pyridyl)piperazin-1-acetyl!-phenoxyacetyl!glycinate.

A solution of methyl N- 4-(bromoacetyl)phenoxyacetyl!-glycinate (0.85 g)in acetonitrile (10 ml) was added to a stirred solution of1-(4-pyridyl)piperazine (0.81 g) in acetonitrile (30 ml). After stirringovernight the solvent was removed in vacuo and the residue partitionedbetween water/ethyl acetate. The organic phase was washed with water,then dried (MgSO₄) and evaporated. The residue was purified by flashchromatography on silica, eluting with 0 to 7.5% v/vmethanol/dichloromethane. Evaporation of the fractions gave the titlecompound, 130 mg, as a foam: NMR (d₆ DMSO) δ 8.58 (1H, t), 8.16 (2H, d),8.01 (2H, d), 7.08 (2H, d), 6.83 (2H, d), 5.75 (1H, s), 4.68 (2H, s),3.92 (2H, d), 3.84 (2H, s), 3.65 (3H, s), 3.34 (4H, t+H₂ O), 2.65 (4H,t); m/e 427 (M+H)⁺ ; calculated for C₂₂ H₂₆ N₄ O₅. 0.5CH₂ Cl₂ : C, 57.6;H, 5.8; N, 11.9. found: C, 57.8; H, 5.7; N, 12.0%.

The starting material was prepared as follows:

(i) To a stirred suspension of 4-(acetyl)phenoxyacetic acid (3.00 g) indichloromethane (40 ml) was added oxalyl chloride (1.62 ml) and 1 dropof DMF. Stirring was continued for 1.5 hours and the clear solution onevaporation gave an oil (I). Triethylamine (4.30 ml) was added slowly toa stirred, cooled (4° C.) suspension of methyl glycinate hydrochloride(1.95 g) in dichloromethane (25 ml) under argon. After stirring for 10minutes, a solution of (I) in dichloromethane (10 ml) was added andstirring continued for a further 2 hours. The precipitate was removed byfiltration and the filtrate concentrated in vacuo. Purification of theresidue by flash chromatography on silica, eluting with 2% v/vmethanol/dichloromethane, gave a solid. Trituration with ether/hexanegave methyl N- 4-(acetyl)-phenoxyacetyl!glycinate, 3.1 g, as whitecrystals: m.p. 120°-121° C.; NMR (d₆ DMSO) δ 8.57 (1H, t), 7.94 (2H, d),7.07 (2H, d), 4.66 (2H, s), 3.92 (2H, s), 3.64 (3H, s), 2.52 (3H, s);m/e 266 (M+H)⁺ ; calculated for C₁₃ H₁₅ NO₅ : C, 58.9; H, 5.7; N, 5.3.found: C, 58.4; H, 5.5; N, 5.0%.

(ii) The product of step (i) (3.00 g) and N-bromosuccinimide (2.02 g) incarbon tetrachloride (50 ml) was heated at reflux temperature for 64hours. The solvent was evaporated and the black residue dissolved inmethanol/ethyl acetate, treated with charcoal, filtered and thenevaporated. The resulting brown oil was purified by flash chromatographyon silica, eluting with dichloromethane. Trituration with hexane gavemethyl N- 4-(bromoacetyl)phenoxyacetyl!glycinate, 0.85 g, as a solid: mpsoftens 109°-111° C.; NMR (d₆ DMSO) δ 8.60 (1H, bt), 7.99 (2H, d), 7.09(2H, d), 4.84 (2H, s), 4.69 (2H, s), 3.91 (2H, d), 3.64 (3H, s).

EXAMPLE 90 Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!ethyl!-phenoxyacetate.

A mixture of methyl 4- 1-(2-methanesulphonyloxyethyl)!-phenoxyacetate(2.0 g) and 1-(4-pyridyl)piperazine (2.26 g) in acetonitrile was heatedat reflux temperature for 25 hours. The solvent was removed in vacuo andthe residue purified by flash chromatography on silica, eluting withsuccessively 2.5, 3, 3.5, and 4% v/v methanol/dichloromethane. Isolationof the desired fractions and trituration with diethyl ether gave thetitle compound, 600 mg: recrystallisation from methanol gave whitecrystals, m.p. 104°-105° C.;

NMR (d₆ DMSO) δ 8.15 (2H, d), 7.15 (2H, d), 6.86 (2H, d), 6.82 (2H, d),4.74 (2H, s), 3.69 (3H, s), 3.30 (4H, t. 2H, m.+H₂ O), 2.71 (2H, m),2.54 (4H, t), m/e 356 (M+H)⁺ calculated for C₂₀ H₂₅ N₃ O₃. 0.25H₂ O: C,66.7; H, 7.1; N, 11.7. found: C, 67.0; H, 7.2; N, 11.4%.

The starting material was prepared as follows:

(i) A mixture of 4-hydroxyphenethyl alcohol (5.37 g), anhydrouspotassium carbonate (5.37 g) and methyl bromoacetate (3.80 ml) inanhydrous acetone (50 ml) was stirred for 18 hours. The mixture, afterfiltration, was evaporated and the residue after purification by flashchromatography on silica, eluting with 2% v/v methanol/dichloromethane,gave methyl 4- 1-(2-hydroxyethyl)!-phenoxyacetate, 5.05 g, as an oil:NMR (CDCl₃) δ 7.15 (2H, d), 6.86 (2H, d), 4.62 (2H, s), 3.84 (2H, m),3.80 (3H, s), 2.81 (2H, t), 1.40 (1H, bt); m/e 210 (M)⁺ ; calculated forC₁₁ H₁₄ O₄ : C, 62.8; H, 6.7. found: C, 62.8; H, 6.8%.

(ii) Methanesulphonyl chloride (0.98 ml) was added dropwise, over 30minutes, to a stirred, cooled (4° C.) solution of the product from step(i) (2.22 g) and triethylamine (1.91 ml) in dichloromethane (35 ml)under argon. After 2 hours, the solvent was evaporated and the residuepartitioned between ethyl acetate (75 ml) and water (20 ml). The organicphase was separated, washed with saturated sodium chloride solution(3×15 ml), dried and evaporated. The residue on purification by flashchromatography on silica, eluting with 45% v/v ethyl acetate/hexane,gave methyl 4- 1-(2-methanesulphonyloxyethyl)!-phenoxyacetate, 2.85 g,as an oil: NMR (CDCl₃) δ 7.16 (2H, d), 6.87 (2H, d), 4.62 (2H, s), 4.38(2H, t), 3.81 (3H, s), 3.00 (2H, t), 2.85 (3H, s); m/e 288 (M+);calculated for C₁₂ H₁₆ O₆ S: C, 50.0; H, 5.6; S, 11.1. found: C, 50.1;H, 5.5; S, 11.0%.

EXAMPLE 91 4- 2- 4-(4-pyridyl)piperazin-1-yl!ethyl!phenoxyacetic aciddihydrochloride.

In a similar manner to Example 71, but starting from the product ofExample 90, there was obtained the title compound in 95% yield: m.p.270°-273° C.; NMR (d₆ DMSO+d₄ acetic acid) δ 8.34 (2H, d), 7.30 (2H, d),7.22 (2H, d), 6.91 (2H, d), 4.67 (2H, s), 4.06 (4H, b), 3.46 (4H, b),3.35 (2H, m), 3.05 (2H, m); m/e 342 (M+H)⁺ ; calculated for C₁₉ H₂₂ N₃O₃. 2HCl: C, 55.0; H, 6.5; N, 10.1. found: C, 54.8; H, 6.2; N, 9.8%.

EXAMPLE 92 Tertiary butyl 4- 2-4-(4-pyridyl)piperazin-1-yl!carbonylmethyl!phenoxyacetate.

In a similar manner to Example 18 step (iv), but starting from tertiarybutyl 4-(carboxymethyl)phenoxyacetate, there was obtained after flashchromatography on silica, eluting with 0 to 5% v/vmethanol/dichloromethane, a gum. Further purification by flashchromatography on neutral alumina, eluting with 1% v/vmethanol/dichloromethane followed by trituration with diethyl ether gavethe title compound in 17% yield as a white solid: m.p. 110°-112° C.;

NMR (d₆ DMSO) δ 8.22(2H, d), 7.15(2H, d), 7.06(2H, d), 6.83(2H, d),4.60(2H, s), 3.70(2H, s), 3.62(4H, bt), 3.38(4H, bt+H₂ O), 1.42(9H, s);m/e 412 (M+H)⁺ ; calculated for C₂₃ H₂₉ N₃ O₄.0.25H₂ O: C, 66.4; H, 7.1;N, 10.1. found: C, 66.4; H, 7.2; N, 10.1%.

The starting material was prepared as follows:

(i) Sodium hydride (50% w/w dispersion in mineral oil, 3.7 g) wastreated under argon with repeated washes of hexane. The oil-free residuewas suspended in dry DMF (100 ml) and 4-hydroxyphenylacetic acid (13.0g) was added portionwise to the stirred cooled (4° C.) mixture. After 30minutes, benzyl bromide (9.2 ml) was added dropwise and, after a further1 hour at 4° C., stirring was continued overnight at ambienttemperature. The solvent was evaporated in vacuo and the residuepartitioned between ethyl acetate and water. The aqueous phase wasre-extracted with further ethyl acetate and the combined organicextracts washed with water and brine, then dried (MgSO₄) and evaporated.The crystalline residue gave benzyl 4-hydroxyphenylacetate, 17.8 g, asoff-white crystals: m.p. 70°-72° C.; NMR (CDCl₃) δ 7.32(5H, m), 7.14(2H,d), 6.76(2H, d), 5.12(2H, s), 3.59(2H, s); m/e 242 (M.sup..)⁺.

(ii) Sodium hydride (50% w/w dispersion in mineral oil, 2.1 g) wastreated under argon with repeated washes of hexane. The oil-free residuewas suspended in dry DMF (130 ml) and the product from step (i) (10 g)added in three portions to the cooled (4° C.) stirred mixture. Stirringwas continued for a further 15 minutes when tertiary butyl bromoacetate(7.0 ml) was added dropwise over 15 minutes. After 1 hour at 4° C., themixture was stirred for 6 hours at ambient temperature. The solvent wasevaporated in vacuo and the residue partitioned between ethyl acetateand water. The aqueous phase was re-extracted with further ethyl acetateand the combined organic phases washed with water and brine, then dried(MgSO₄) and evaporated. The residue, after purification by flashchromatography on silica eluting with dichloromethane, gave tertiarybutyl 4-(benzyloxycarbonylmethyl)phenoxyacetate, 7.5 g, as a colourlessoil: NMR (CDCl₃) d 7.31(5H, m), 7.20(2H, m), 6.85(2H, m), 5.12(2H, s),4.49(2H, s), 3.60(2H, s), 1.48(9H, s); m/e 356 (M.sup..)⁺.

(iii) In a similar manner to Example 18 step (iii) but starting from theproduct of step (ii) above was prepared tertiary butyl4-(carboxymethyl)phenoxyacetate in 96% yield as a white crystallinesolid: m.p.78°-80° C.; NMR (d₆ DMSO) δ 7.15(2H, d), 6.82(2H, d),4.60(2H, s), 3.48(2H, s), 1.43(9H, s); m/e 266 (M.sup.·)⁺ ; calculatedfor C₁₄ H₁₈ O₅.0.75H₂ O: C, 60.1; H, 7.0. found: C, 59.9; H, 7.2%.

EXAMPLE 93 4- 2-4-(4-pyridyl)piperazin-1-yl!carbonylmethyl!phenoxy-acetic acid,dihydrochloride.

A solution of the product from Example 92 (50 mg) in a mixture ofdioxane (1 ml), water (2 ml) and 1 molar hydrochloric acid solution(0.61 ml) was heated overnight at 90° C. The resulting solution, ondilution with water and freeze-drying, gave the title compound, 30 mg,as a yellow foam: NMR (d₆ DMSO+d₄ acetic acid) δ 8.31(2H, d), 7.24(2H,d), 7.18(2H, m), 6.87(2H, m), 4.64(2H, s), 3.96(4H, t), 3.72(2H, s),3.32(4H, t); m/e 356 (M+H)⁺ ; calculated for C₁₉ H₂₁ N₃ O₄.2HCl.2.5H₂ O:C, 48.2; H, 5.9; N, 8.9. found C, 48.5; H, 6.0; N, 8.8%.

EXAMPLE 94 Methyl 4- 2-4-(2-methylpyrid-4-yl)piperazin-1-yl!acetyl!phenoxyacetate

Methyl 4-bromoacetylphenoxyacetate (1.72 g) was added to a stirredmixture of 1- 4-(2-methylpyridyl)!piperazine dihydrochloride (1.5 g) andtriethylamine (2.5 ml) in acetonitrite (25 ml). Stirring was continuedovernight when the solvent was removed in vacuo. Purification by flashchromatography, first on silica eluting with 10% v/vmethanol/dichloromethane and then on neutral alumina eluting with 1% v/vmethanol/dichloromethane, gave the title compound, 418 mg, as a whitesolid: m.p. 155°-157° C.; NMR (d₆ DMSO) δ 8.00(3H, m), 7.04(2H, d),6.70(1H, d), 6.64(1H, dd), 4.92(2H, s), 3.83(2H, s), 3.71(3H, s),3.30(4H, b+H₂ O), 2.61(4H, t), 2.32(3H, s); m/e 384 (M+H)⁺ ; calculatedfor C₂₁ H₂₅ N₃ O₄ : C, 65.8; H, 6.6; N, 11.0. found: C, 65.4; H, 6.8; N,10.9%.

The starting material was prepared as follows:

(i) A mixture of 4-chloro-2-picoline (5 g) and 1-benzylpiperazine (13.6ml) in xylene (50 ml) was heated at reflux temperature for 18 hours. Thesolution was cooled and the solid precipitate removed by filtration andthe filtrate concentrated in vacuo. Purification by flash chromatographyon silica, eluting with 20% v/v methanol/dichloromethane gave 4-4-(2-picolyl)!-1-benzylpiperazine, 9.54 g, as a light fawn crystallinesolid: m.p. 94°-95° C.; NMR (CDCl₃) δ 8.15(1H, d), 7.30(5H, m), 6.51(2H,m), 3.57(2H, s), 3.44(4H, t), 2.57(4H, t), 2.46(3H, s); m/e 268 (M+H)⁺ ;calculated for C₁₇ H₂₁ N₃ : C, 76.4; H, 7.9; N, 15.7. found: C, 75.7; H,8.1; N, 15.7%.

(ii) 10% w/w Palladium on charcoal (1.5 g) was added to a stirredsolution of the product of step (i) (9.00 g) and 2 molar hydrochloricacid (34 ml) in methanol (180 ml) and the mixture was hydrogenated atroom temperature and pressure until the theoretical amount of hydrogenhad been taken up. Charcoal was added, the mixture stirred for 5 minutesthen filtered through diatomaceous earth and the filtrate on evaporationto dryness gave 1- 4-(2-methylpyridyl)!piperazine dihydrochloride, 10.6g, as a fawn solid: m.p. 64°-68° C. NMR (d₆ DMSO) δ8.20(1H, d), 7.18(1H,d), 7.12(1H, dd), 3.92(4H, t), 3.19(4H, t), 2.51(3H, s+DMSO); m/e 178(M+H)⁺ ; calculated for C₁₀ H₁₅ N₃.2HCl.0.75H₂ O: C, 45.5; H, 7.0; N,15.9. found: C, 45.3; H, 7.0; N, 15.8%.

EXAMPLE 95 4- 2-4-(2-methylpyrid-4-yl)piperazin-1-yl!acetyl!-phenoxyacetic acid,dihydrobromide.

A mixture of the product of Example 94 (160 mg), 48% w/v hydrobromicacid (0.25 ml) and dioxane (1 ml) in water (3 ml) were heated at 90° C.for 30 minutes. The solution was cooled, further water added and themixture freeze-dried. Trituration of the residue with absolute ethanolgave the title compound, 50 mg, as a fawn solid: m.p. 146°-148° C.; NMR(d₆ DMSO+d₄ acetic acid) δ 8.17(1H, d), 7.95(2H, d), 7.09(4H, m),4.94(2H, s), 4.78(2H, s), 3.99(4H, b), 3.07(1H, q), 2.46(3H, s),1.17(1.5H, t); m/e 370 (M+H)⁺ ; calculated for C₂₀ H₂₃ N₃ O₄.2HBr.H₂O.0.5C₂ H₅ OH: C, 44.1; H, 5.3; N, 7.3. found: C, 44.0; H, 5.4; N, 7.2%.

EXAMPLE 96 Methyl 4- 1-(4-pyridyl)piperidin-4-yl!oxyphenoxyacetate

Diethylazodicarboxylate (0.47 ml) was added dropwise over 30 minutes toa stirred mixture of 1-(4-pyridyl)-4-piperidinol (534 mg), methyl4-hydroxyphenoxyacetate (546 mg), triphenylphosphine (787 mg) and dryTHF (30 ml) in an atmosphere of argon and cooled to 4° C. After 1 hourat 4° C., the mixture was allowed to reach ambient temperature andstirred for 48 hours. The solvent was removed by evaporation and theresidue purified by flash chromatography on silica eluting with 5% v/vmethanol/dichloromethane. Recrystallisation from ethyl acetate/hexanegave the title compound, 532 mg, as a white solid: m.p. 74°-76° C.; NMR(d₆ DMSO) δ 8.15(2H, bd), 6.89(6H, m), 4.71(2H, s), 4.50(1H, m),3.70(2H, m), 3.69(3H, s), 3.23(2H, m), 1.96(2H, m), 1.62(2H, m); m/e 343(M+H)⁺ ; calculated for C₁₉ H₂₂ N₂ O₄ : C, 66.7; H, 6.5; N, 8.2. found:C, 66.2; H, 6.7; N, 8.2%.

EXAMPLE 97 4- 1-(4-pyridyl)piperidin-4-yl!oxyphenoxyacetic acid

Following the method of Example 2, but starting from the product ofExample 96, the title compound was prepared in 85% yield: m.p. 288°-291°C.; NMR (NaOD+d₆ DMSO) δ 7.97(2H, d), 6.77(4H, m), 6.69(2H, d), 4.35(1H,m), 4.19(2H, s), 3.53(2H, m), 3.08(2H, m), 1.82(2H, m), 1.49(2H, m); m/e329 (M+H)⁺ ; calculated for C₁₈ H₂₀ N₂ O₄ : C, 65.8; H, 6.1; N, 8.5.found: C, 65.7; H, 6.3; N, 8.4%.

EXAMPLE 98 Methyl 4- 1-(4-pyridyl)piperidin-4-yl!-methoxyphenoxyacetate

Following the method of Example 96, but starting from4-(4-hydroxymethylpiperidin-1-yl)pyridine, the title compound wasprepared in 18% yield: m.p. 127°-129° C.; NMR (d₆ DMSO) δ 8.12(2H, d),6.84(4H, s), 6.81(2H, d), 4.70(2H, s), 3.96(2H, bd), 3.79(2H, d),3.70(3H, s), 2.88(2H, dt), 2.01(1H, m), 1.82(2H, bd), 1.30(2H, m), m/e357 (M+H)⁺ ; calculated for C₂₀ H₂₄ N₂ O₄.0.5H₂ O: C 65.7; H 6.9; N, 7.7found: C, 66.1; H, 6.9; N, 7.8%.

EXAMPLE 99 4- 1-(4-pyridyl)piperidin-4-yl!methoxyphenoxyacetic acid.

Following the method of Example 2 but starting from the product ofExample 98, the title compound was prepared in 86% yield: m.p. 278°-281°C.; NMR (d₆ DMSO+TFA) δ 8.09(2H, t), 7.08(2H, d), 6.78(4H, s), 4.50(2H,s), 4.20(2H, bd), 3.74(2H, d), 3.17(2H, bt), 2.12(1H, m), 1.91(2H, dm),1.32(2H, m); m/e 343 (H+H)⁺ ; calculated for C₁₉ H₂₂ N₂ O₄.0.25H₂ O: C,65.8; H, 6.5; N, 8.1. found: C, 66.0; H, 6.6; N, 8.0%.

EXAMPLE 100 Methyl 4- 2-1-(4-pyridyl)piperidin-4-yl!ethoxyl!phenoxy-acetate

Following the method of Example 96, but starting from4-(4-hydroxyethylpiperidin-1-yl)pyridine, the title compound wasprepared in 65% yield: m.p. 86°-88° C.; NMR (d₆ DMSO) δ 8.11(2H, d),6.85(4H, s), 6.79(2H, d), 4.70(2H, s), 3.96(2H, t), 3.92(2H, bd),3.69(3H, s), 2.81(2H, dt), 1.78(2H, bd), 1.73(1H, m), 1.65(2H, q),1.20(2H, m); m/e 371 (M+H)⁺ ; calculated for C₂₁ H₂₆ N₂ O₄ : C, 68.1; H,7.1; N, 7.6. found: C, 67.5; H, 7.3; N, 7.5%.

EXAMPLE 101 4- 2- 1-(4-pyridyl)piperidin-4-yl!ethoxy!phenoxyacetic acid

Following the method of Example 2, but starting from the product ofExample 100, the title compound was prepared in 74% yield: m.p.247°-249° C.; NMR (d₆ DMSO+TFA) δ 8.19(2H, t), 7.19(2H, d), 6.38(4H, s),4.60(2H, s), 4.25(2H, bd), 4.01(2H, t), 3.20(2H, dr), 1.93(3H, m),1.70(2H, q), 1.28(2H, m); m/e 357 (M+H)⁺ ; calculated for C₂₀ H₂₄ N₂ O₄: C, 67.4; H, 6.8; N, 7.9. found: C, 67.0; H, 6.8; N, 7.7%.

EXAMPLE 102 Methyl 3- 4-1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!-propionate

Following the method of Example 96, but starting from4-(4-hydroxymethylpiperidin-1-yl)pyridine and methyl3-(4-hydroxyphenyl)propionate, the title compound was prepared in 14%yield: m.p. 96.5°-98.5° C.; NMR (d₆ DMSO) δ 8.13(2H, d), 7.11(2H, d),6.83(4H, m), 3.97(2H, dm), 3.81(2H, d), 3.56(3H, s), 2.87(2H, dr),2.77(2H, t), 2.57(2H, t), 2.01(1H, m), 1.84(2H, m), 1.30(2H, m); m/e 355(M+H)⁺ ; calculated for C₂₁ H₂₆ N₂ O₃.0.75H₂ O: C, 68.5; H, 7.2; N, 7.8.found: C, 68.5; H, 7.5; N, 7.6%.

EXAMPLE 103 3- 4- 1-(4-pyridyl)piperidin-4-yl!methoxyphenyl!-propionicacid

Following the method of Example 2, but starting from the product ofExample 161, the title compound was prepared in 80% yield: m.p.303°-307° C.; NMR (d₆ DMSO+TFA) δ 8.20(2H, d), 7.25(6H, m), 4.31(2H,dm), 3.88(2H, d), 3.27(2H, bt), 2.82(2H, t), 2.52(2H, t), 2.25(1H, m)2.00(2H, bd), 1.40(2H, m); m/e 341 (M+H)⁺ ; calculated for C₂₀ H₂₄ N₂O₃.0.25H₂ O: C, 69.6; H, 7.2; N, 8.1. found: C, 69.6; H, 7.2; N, 8.0%.

EXAMPLE 104 Methyl 4-1-(4-pyridyl)piperidin-4-yl!carboxamido!-phenoxyacetate, hydrochloride

Thionyl chloride (5 ml) was added dropwise over ten minutes to a stirredsuspension of 1-(4-pyridyl)-4-piperidinecarboxylic acid (2.06 g) in drydichloromethane (20 ml) at 4° C. After 1 hour at 4° C., the mixture wasallowed to reach ambient temperature and stirred for 16 hours. Thesolvent was removed by evaporation and the residue dried under highvacuum to give a solid foam (2.84 g).

Triethylamine (0.70 ml) was added to a stirred suspension of methyl4-aminophenoxyacetate hydrochloride (544 mg) in dry dichloromethane (10ml). After stirring for 1 hour, the mixture was cooled to 4° C., and thefoam (0.71 g) added. After 1 hour at 4° C. the mixture was allowed toreach ambient temperature and stirred for 16 hours. The precipitatedsolid was collected, washed with dichloromethane and, onrecrystallisation from water, gave the title compound, 744 mg: m.p.233°-234.5° C.; NMR (d₆ DMSO) δ 13.56(1H, b), 9.98(1H, s), 8.21(2H, d),7.51(2H, d), 7.20(2H, d), 6.85(2H, d), 4.72(2H, s), 4.25(2H, bd),3.69(3H, s), 3.27(2H+H₂ O), 2.78(1H, m), 1.97(2H, m), 1.67(2H, m); m/e370 (M+H)⁺ ; calculated for C₂₀ H₂₃ N₃ O₄.HCl: C, 59.2; H, 6.0; N, 10.4.found: C, 58.8; H, 6.1; N, 10.3%.

EXAMPLE 105 4-4- 1-(1-(4-pyridyl)piperidin-4-yl!carboxamido!-phenoxyacetic acid

Following the method of Example 2, but starting from the product ofExample 104, the title compound was prepared in 69% yield: m.p.285°-287° C.; NMR(NaOD) δ 8.30(2H,d), 7.44(2H,d), 7.07(2H,d),7.04(2H,d), 4.60(2H,s), 4.14(2H,bd), 3.11(2H,dt), 2.81(1H,m),2.11(2H,bd), 1.88(2H,dq); m/e 356(M+H)⁺ ; calculated for C₁₉ H₂₁ N₃ O₄.H₂ O: C, 61.1; H, 6.2; N, 11.3. found: C, 60.9; H, 6.2; N, 11.0%.

EXAMPLE 106 Methyl 4- 2-(1-(4-pyridyl)piperidin-4-yl!-acetamido!phenoxyacetate.

To a stirred solution of 1-(4-pyridylpiperidin-4-yl)acetic acidhydrochloride (400 mg) in dry DMF (5 ml) was addedN,N'-diisopropylethylamine (1.1 ml), HOBT (240 mg),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(600 mg). After 15 minutes methyl 4-aminophenoxyacetate (280 mg) wasadded and stirring continued overnight. The reaction mixture was addedto ethyl acetate (100 ml) and this mixture washed with water, 10% w/vsodium hydrogen sulphate solution and brine, then dried (MgSO₄) andevaporated. Purification of the resulting gum by flash chromatography,first on silica eluting with 0 to 5% v/v methanol/dichloromethane andthen on neutral alumina eluting with 2% v/v methanol/dichloromethanegave, on trituration with diethyl ether the title compound, 55 mg, as anoff-white solid: m.p. 155°-157° C.; NMR(d₆ DMSO) δ 9.74(1H,s),8.11(2H,d), 7.48(2H,d), 6.86(2H,d), 6.79(2H,d), 4.73(2H,s), 3.91(2H,bd),3.70(3H,s), 2.84(2H,dt), 2.21(2H,d), 2.03(1H,m), 1.72(2H,bd),1.22(2H,dq); m/e 384(M+H)⁺ ; calculated for C₂₁ H₂₅ N₃ O₄. 0.5 H₂ O: C,64.5; H, 6.6; N, 10.7. found: C, 64.7; H, 6.8; N, 10.8%.

The starting material was prepared as follows:

(i) A stirred suspension of sodium hydride (50% dispersion in mineraloil, 4.8 g, 0.1Moles) in dimethoxyethane (300 ml) was ice-cooled andtreated under an atmosphere of argon with triethyl phosphonoacetate(19.82 ml, 0.1Moles), added dropwise. Stirring was continued for 1 hourduring which time the temperature of the mixture was maintained <5° C.The cooling bath was removed and N-benzylpiperidone (17.85 ml, 0.1Moles)was added dropwise. The mixture was stirred overnight at roomtemperature, then diluted with water (500 ml) and extracted with ether(3×200 ml). The combined organic extracts were washed with water (200ml) and saturated brine (100 ml), dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by chromatography (flashcolumn, eluted with hexane/ethyl acetate; 3:2) to give ethyl4-carboxymethylene-N-benzylpiperidine ester (5.52 g) as a yellow oil;NMR (CDCl₃): 1.1 (t,3H), 2.2 (t,2H), 2.4 (m,4H), 3.4 (s,2H), 4.0 (q,2H),5.6 (s,1H), 7.2 (m,5H); m/e 260 (H+H)⁺.

(ii) A solution of ethyl 4-carboxymethylene-N-benzylpiperidine ester(5.5 g, 21 mMoles) in ethanol (250 ml)was stirred with 10% palladium oncarbon under an atmosphere of hydrogen until a total of 950 ml ofhydrogen had been consumed. An additional quantity of 10% palladium oncarbon (500 mg) was added and stirring was continued for hours to removeresidual starting material. The mixture was filtered and concentratedunder reduced pressure to give ethyl 4-carboxymethylpiperidine ester(3.31 g) as a slightly green oil which was used without furtherpurification; NMR (CDCl₃): 1.0-1.2 (m,2H), 1.25 (t,3H), 1.7 (s,2H), 1.9(m,1H), 2.2 (d,2H), 2.6 (td,2H), 3.05 (dt,2H), 4.0 (q,2H); m/e 172(H+H)⁺.

(iii) A mixture of ethyl 4-carboxymethylpiperidine (3.25 g),triethylamine (5.28 ml), 4-chloropyridine hydrochloride (2.85 g) andxylene (100 ml) was heated at reflux temperature overnight. The mixturewas cooled, the precipitate removed by filtration and the filtrateevaporated. A solution of the residue in dichloromethane was washed withwater, then dried (MgSO₄) and evaporated. Purification by flashchromatography on silica, eluting with 10% v/v methanol/dichloromethane,gave ethyl 1-(4-pyridylpiperidin-4-yl)acetate, 2.15 g, as an oil:NMR(CDCl₃) δ 8.23(2H,d), 6.64(2H,d), 4.26(2H,q), 3.88(2H,dm),2.89(2H,dt), 2.27(2H,d), 2.05(1H,m), 1.83(2H,dm), 1.36(2H,dq),1.27(3H,t); m/e 249(H+H)⁺.

(iv) A mixture of the product from step (iii) (2.20 g), 1 molarhydrochloric acid (35.5 ml) and dioxane (100 ml) was heated at 95° C.for 3 hours. The resulting solution, on freeze-drying, gave1-(4-pyridylpiperidin-4-yl)acetic acid hydrochloride, 2.3 g, as alight-brown powder: m.p. 105°-108° C.; NMR(d₆ DMSO) δ 13.57(1H,b),8.18(2H,d), 7.17(2H,d), 4.21(2H,bd), 3.17(2H,dt), 2.21(2H,d),2.09(1H,m), 1.83(2H,dm); 1.22(2H,dq); m/e 221(H+H)⁺ ; calculated for C₁₂H₁₆ N₂ O₂. HCl. 1.25 H₂ O: C, 51.6; H, 7.0; N, 10.0; Cl, 12.7. found C,51.7; H, 7.0; N, 9.8; Cl, 12.2%.

EXAMPLE 107 4- 2- 1-(4-pyridyl)piperidin-4-yl!acetamido!phenoxyaceticacid dihydrochloride

A mixture of the product from Example 106 (30 mg), 1 molar hydrochloricacid (0.40 ml), water (2 ml) and dioxane (1 ml) was heated at 95° C. for1 hour. The resulting solution, on freeze-drying and trituration of theresidue with ether, gave the title compound, 25 mg, as a light brownsolid: m.p. 158°-162° C.; NMR(d₆ DMSO+d₄ acetic acid) 8.17(2H,d),7.49(2H,d), 7.20(2H,d), 6.85(2H,d), 4.61(2H,s), 4.23(2H,bd),3.21(2H,bt), 2.21(3H,m); 1.86(2H,bd+acetic acid), 1.28(2H,bq); m/e 370(M+H)⁺ ; calculated for C₂₀ H₂₃ N₃ O₄. 2HCl. 1.25 H₂ O: C, 51.7; H, 5.9;N, 6.0. found: C, 51.6; H, 6.0; N, 9.2%.

EXAMPLE 108 4- 1-(4-pyridyl)piperidin-4-yl!aminocarbonyl!-phenoxyaceticacid dihydrochloride

Following the method of Example 107, but starting from tertiary butyl 4-1-(4-pyridyl)piperidin-4-yl!aminocarbonyl!-phenoxyacetate (50 mg), butwith the removal of the insoluble precipitate before freeze-drying, thetitle compound was prepared in 50% yield: m.p. 278°-280° C.; NMR(d₆DMSO+d₄ acetic acid) δ 8.19(2H,d), 7.82(2H,d), 7.20(2H,d), 6.98(2H,d),4.74(2H,s), 4.23(3H,m), 3.38(2H,bt), 2.04(2H,m), 1.64(2H,m); m/e 356(M+H)⁺ ; calculated for C₁₉ H₂₁ N₃ O₄. 2HCl. 1.25 H₂ O: C, 50.6; H, 5.7;N, 9.3. found: C, 50.6; H, 5.7; N, 9.2%.

The starting material were prepared as follows.

(i) Acetyl chloride (3.95 ml) was added dropwise to a stirred solutionof 4-amino1-benzylpiperidine (10.0 g) and triethylamine (7.7 ml) in drydichloromethane (100 ml) at 4° C. The mixture was allowed to reachambient temperature and stirred for 16 hours. Water was then added, theorganic phase separated and dried (MgSO₄), and removal of the solvent byevaporation gave 4-acetylamino-1-benzylpiperidine, 10.23 g, as a lightbrown solid which was used without further purification: NMR (CDCl₃) δ7.29(5H,m), 5.29(1H,b), 3.79(1H,m), 3.49(2H,s), 2.80(2H,dm),2.12(2H,dt), 1.95(3H,s), 191(2H,dm), 1.46(2H,dq); m/e 233 (M+H)⁺.

(ii) 10% w/w Palladium on charcoal (1.5 g) was added to a solution ofthe product from step (i) (10.0 g), 1 molar hydrochloric acid (21.5 ml)and methanol (150 ml) and the mixture hydrogenated at room temperatureand pressure until the theoretical amount of hydrogen had been taken up.Charcoal was added, the mixture stirred for 1 hour then filtered throughdiatomaceous earth and the filtrate evaporated to dryness giving4-acetylaminopiperidine hydrochloride, 8.64 g, as a sticky foam: NMR(CDCl₃ +d₆ DMSO). δ 9,72(1H,b), 9.02(1H,b), 7.40(1H,bd), 3.87(1H,m),3.30(2H,m), 2.81(2H,m), 1.86(4H,m), 1.80(3H,s); m/e 143 (M+H)⁺.

(iii) A mixture of the product from step (ii) (1.79 g), 4-chloropyridinehydrochloride (1.50 g), sodium hydrogen carbonate (2.86 g) in 3-methyl1-butanol (25 ml) was heated at reflux temperature for 16 hours. Thecooled mixture was filtered and the filtrate concentrated in vacuo.Purification of the residue by flash chromatography on silica, elutingwith methanol/dichloromethane (1:2 v/v) gave4-acetylamino-1-(4-pyridyl)piperidine as a foam, 0.69 g: NMR(d₆ DMSO) δ8.10(2H,d), 7.80(1H,bd), 6.80(2H,dd), 3.82(3H,m), 2.93(2H,dt),1.78(3H,s), 1.77(2H,m), 1.33(2H,dq); m/e 220 (M+H)⁺.

(iv) The product from step (iii) (0.52 g) in 1 molar hydrochloric acid(11.9 ml) was heated at 95° C. for 5 hours. The solvent was evaporatedand the residue, on drying over potassium hydroxide in vacuo gave4-amino-1-(4-pyridyl)piperidine trihydrochloride hydrate, 0.70 g as alight brown solid: m.p. >300° C.; NMR (d₆ DMSO) δ 8.28(4H,m),7.22(2H,d), 4.27(2H,bd), 3.5 to 3.15(3H +H₂ O), 2.09(2H,m), 1.59(2H,dq);m/e 178(M+H)⁺ ; calculated for C₁₀ H₁₅ N₃. 3HCl. 0.75 H₂ O: C, 40.0; H,6.5; N, 14.0. found: C, 40.4; H, 6.3; N, 13.5%.

(v) A mixture of benzyl 4-hydroxybenzoate (4 g), t-butyl bromoacetate(3.7 g), powdered anhydrous potassium carbonate (2.4 g) and acetone (100ml) was heated at reflux for 3 days. The reaction mixture was cooled andthen filtered and the filtrate evaporated to dryness to give a viscousoil (6.37 g). A portion of this oil (3.4 g) was dissolved in methanol(30 ml) and ammonium formate (4 g) was added. The resultant solution wascovered with a blanket of argon before a slurry of 10% Pd on C (100 mg)in methanol (5 ml), also under argon, was added. The reaction mixturewas stirred at room temperature for 18 hours then the catalyst wasfiltered off through a pad of kieselguhr and washed with ethanol andwater. The combined filtrate and washings were evaporated to dryness andthe residue was partitioned between dichloromethane and aqueous sodiumbicarbonate. The aqueous layer was separated, washed withdichloromethane and then carefully acidified with dilute aqueous citricacid solution. A solid precipitated which was collected, washed withwater and air-dried to give 4-t-butoxycarbonylmethoxybenzoic acid (1.45g), as a white crystalline solid: m.p. 119°-121° C.

(vi) Following the method of Example 106, but starting from the productof step (v) and the product from step (iv) and purification by flashchromatography on silica eluting with 0-5% v/v methanol/dichloromethanethere was obtained tertiary butyl 4-1-(4-pyridyl)piperidin-4-yl!aminocarbonyl!phenoxyacetatehexafluorophosphate in 49% yield as a white solid: m.p. 196°-198° C.;NMR(d₆ DMSO) δ 8.21(2H,d), 8.18(1H,d), 7.80(2H,d), 7.19(2H,d),6.95(2H,d), 4.72(2H,s), 4.20(3H,m), 3.5-3.1(4H+H₂ O), 1.98(2H,1.59(2H,m), 1.42(9H,s); m/e 412 (M+H)⁺ ; calculated for C₂₃ H₂₉ N₃ O₄.HPF₆ : C, 49.6; H, 5.4; N, 7.5. found: C, 49.1; H, 5.5; N, 7.3%. Thefree base was generated by flash chromatography on neutral aluminaeluting with 1% v/v methanol dichloromethane and used in the preparationof the acid.

EXAMPLE 109 4-1-(4-pyridyl)piperidin-4-yl!methylaminocarbonyl!-phenoxyacetic acid

Following the method of Example 107, but starting from tertiary butyl 4-1-(4-pyridyl)piperidin-4-yl!methylaminocarbonyl!-phenoxyacetate, thetitle compound was prepared in 95% yield: m.p. 84°-86° C.; NMR (d₆ DMSO)δ 8.38(1H,t), 8.18(2H,d), 7.81(2H,d), 7.19(2H,d), 6.95(2H,d),4.73(2H,s), 4.20(2H,bd), 3.8 to 3.0(H₂ O), 1.99(1H,m), 1.84(2H,bd),1.21(2H,m); m/e 370 (M+H)⁺.

The starting material was prepared as follows:

(i) Following the method of Example 108 step (i), but starting from1-tertiarybutyloxycarbonylpiperidin-4-ylmethylamine tosylate there wasprepared N- (1-tertiarybutyloxycarbonylpiperidin-4-yl)-methyl!acetamidein 95% yield as an oil which slowly crystallised: NMR (CDCl₃) δ5.52(1H,b), 4.12(2H,bd), 3,14(2H,m), 2.68(2H,dt), 1.98(3H,s),1.67(3H,m), 1.44(9H,s), 1.12(2H,dq); m/e 257 (M+H)⁺.

The product was used in step (ii) without further purification.

(ii) A solution of the product from step (i) (6.50 g)in trifluoroaceticacid (50 ml) was stirred overnight. The solvent was evaporated and theresidue, on purification by flash chromatography on neutral alumina,eluting with 10% v/v methanol/dichloromethane gave N-4-piperidinylmethyl!acetamide, 3.78 g, as a yellow oil: NMR (d₄ aceticacid) δ 3.22(2H,bd), 2.96(2H,d), 2.81(2H,dt), 1.83(3H,s), 1.76(2H,bd),1.67(1H,m), 1.26(2H,dq); m/e 157 (M+H)⁺.

(iii) Following the method of Example 106 step (i), but starting fromthe product of (ii) above and purification by flash chromatography onsilica eluting with 20 to 33% v/v methanol/dichloromethane there wasobtained 4-(4-acetylaminomethylpiperidin-1-yl)pyridine in 28% yield as agummy solid: NMR (d₆ DMSO) δ 8.18(2H,d), 7.90(1H,t), 7.07(2H,d),4.12(2H,bd), 3.05(2H,dt), 2.95(2H,t), 1.80(3H,s), 1.77(3H,m),1.13(2H,m); m/e 234 (M+H)⁺.

(iv) Following the method of Example 108 step (iv), but starting fromthe product of (iii) above, there was obtained4-(4-aminomethylpiperidin-1-yl)pyridine in 95% yield as a yellow gum:NMR (d₆ DMSO) δ 8.26(4H,m), 7.21(2H,d), 4.26(2H,bd), 3.19(2H,dt),2.74(2H,t), 2.05(1H,m), 1.92(2H,bd), 1.26(2H,dq); m/e 192 (M+H)⁺.

(v) Following the method of Example 106, but starting from the productof Example 108 step (v) and the product from step (iv) above andpurification by flash chromatography on silica, eluting with 0 to 5% v/vmethanol/dichloromethane and trituration with diethyl ether there wasobtained tertiary butyl 4-1-(4-pyridyl)piperidin-4-yl)!-methylaminocarbonyl!phenoxyacetatehexafluorophosphate in 35% yield as a white solid: m.p. 182°-184° C.;NMR (d₆ DMSO) δ 13.11(1H,b), 8.37(1H,t), 8.17(2H,d), 7.80(2H,d),7.19(2H,d), 6.95(2H,d), 4.72(2H,s), 4.21(2H,bd), 3.19(4H,m), 2.00(1H,m),1.86(2H,m), 1.43(9H,s), 1.21(2H,m); m/e 426(M+H)⁺ ; calculated for C₂₄H₃₁ N₃ O₄. HPF₆. 0.5 H₂ O: C, 49.6; H, 5.7; N, 7.2; P, 5.4. found: C,49.6; H, 5.7; N, 7.1;

EXAMPLE 110 4- 1-(4-pyridyl)piperidin-4-yl!carboxamido!phenylacetic acid

Following the method of Example 2, but starting from methyl 4-1-(4-pyridyl)piperidin-4-yl!carboxamido!phenylacetate hydrochloride thetitle compound was prepared in 93% yield: m.p. 281°-282° C.; NMR (d₆DMSO) δ 9.87(1H,s), 8.13(2H,d), 7.51(2H,d), 7.16(2H,d), 6.83(2H,dd),4.00(2H,dm), 3.49(2H,s), 2.90(2H,dt), 2.61(1H,m), 1.87(2H,dd),1.66(2H,dq); m/e 340 (M+H)⁺ ; calculated for C₁₉ H₂₁ N₃ O₃ : C, 67.2; H,6.2; N, 12.4. found: C, 67.4; H, 6.2; N, 12.4%.

The starting material was prepared as follows:

(i) Following the method of Example 104, but starting from methyl4-aminophenylacetate hydrochloride, methyl 4-1-(4-pyridyl)piperidin-4-yl!carboxamido!phenylacetate hydrochloride wasprepared in 78% yield: m.p. 235°-236.5° C.; NMR (d₆ DMSO) δ 13.61(1H,b),10.10(1H,s), 8.21(2H,d), 7.55(2H,d), 7.21(2H,d), 7.16(2H,d),4.28(2H,dm), 3.60(5H,s), 3.30(2H,m+H₂ O), 2.81(1H,m), 1.98(2H,m),1.67(2H,m); m/e 354(M+H)⁺ ; calculated for C₂₀ H₂₃ N₃ O₃. HCl: C, 61.6;H, 6.2; N, 10.8. found: C, 61.7; H, 6.3; N, 10.6%.

EXAMPLE 111 4-Methyloxycarbonylmethylaminophenyl1-(4-pyridyl)-piperidin-4-yl!acetate

Thionyl chloride (1 ml) was added dropwise to a stirred suspension of1-(4-pyridyl)piperidin-4-yl!acetic acid (300 mg) in dry dichloromethane(5 ml) and the mixture stirred for 4 hours. The solvent was evaporatedand the residue triturated with hexane and dried under high vacuum overpotassium hydroxide to give a solid foam.

A solution of the foam in dry dichloromethane (5 ml) was added dropwiseto a stirred solution of methyl N-(4-hydroxyphenyl)-glycinate (210 mg)and triethylamine (0.33 ml) in dry dichloromethane (10 ml) and themixture stirred for 16 hours. The mixture was diluted withdichloromethane, washed with water, dried and evaporated. Purificationby flash chromatography on silica, eluting with 0-10% v/vmethanol/dichloromethane and trituration of the resulting gum withdiethyl ether gave the title compound, 80 mg, as a white solid: m.p.120°-122° C. NMR(d₆ DMSO) δ 8.13(2H,d) 6.84(2H,d) 6.81(2H,d) 6.54(2H,d),6.01(1H,t), 3.96(2H,bd), 3.90(2H,d), 3.66(3H,s), 2.90(2H,dt),2.50(2H,d+DMSO), 2.07(1H,m), 1.81(2H,bd), 1.30(2H,dq); m/e 384(M+H)⁺ ;calculated for C₂₁ H₂₅ N₃ O₄. 0.5 H₂ O: C, 64.3; H, 6.6; N, 10.7. found:C, 64.2; H, 6.3; N, 10.7%.

EXAMPLE 112 Methyl 4- 2-1-(4-pyridyl)piperidin-4-yl!acetyl!-phenoxyacetate

Oxalyl chloride (2.40 ml) was added to a stirred suspension of1-(4-pyridyl)piperidin-4-yl!acetic acid hydrochloride hydrate (1.25 g)in dry dichloromethane under argon. A few drops of dry DMF were addedand the mixture stirred for 30 minutes to give a clear solution. Thesolvent was removed in vacuo and the residue dried. The resulting solidfoam was suspended in dichloroethane (40 ml), the suspension cooled to4° C. and with stirring, aluminium chloride (3.21 g) added. After 30minutes the mixture was allowed to warm to ambient temperature whenmethyl phenoxyacetate (1.16 ml) was added and stirring continued for afurther 2.5 hours. The mixture was added to an ice-water mixture towhich was added dichloromethane. The aqueous phase was adjusted to pH₇and the solid removed by filtration. The filtrate was extracted threetimes with dichloromethane and the extracts dried (MgSO₄). Evaporationof the solvent gave a clear oil which crystallised on addition of ether.The solid was collected and on recrystallisation from methyl acetategave the title compound, 1.06 g: m.p. 137°-138° C.; NMR (d₆ DMSO) δ 8.11(2H, b). 7.94 (2H, d), 7.03 (2H, d), 6.78 (2H, bd), 4.91 (2H, s), 3.90(2H, d), 3.71 (3H, s), 2.91 (2H, d), 2.85 (2H, dt), 2.12 (1H, m), 1.75(2H, bd), 1.26 (2H, dq); m/e 369 (M+H)⁺ ; calculated for C₂₁ H₂₄ N₂ O₄ :C, 68.5; H, 6.6; N, 7.6. found C, 68.2; H, 6.5; N 7.5%.

The starting 1-(4-pyridyl)piperidin-4-yl!acetic acid hydrochloridehydrate is described in Example 106 steps (i) and (ii).

EXAMPLE 113 4- 2- 1-(4-pyridyl)piperidin-4-yl!acetyl!phenoxyacetic acidhydrochloride.

A mixture of the product of Example 112 (300 mg), dioxan (10 ml) and 1molar hydrochloric acid (2.7 ml) were stirred for 80 hours at ambienttemperature. The solvent was removed in vacuo and a little water added.The resulting solid was collected, washed with water and, after drying,gave the title compound, 170 mg: m.p. 239°-241° C.;

NMR (D₂ O) δ 8.17 (2H, d), 8.15 (2H, d), 7.36 (2H, d), 7.20 (2H, d),5.01 (2H, s), 4.33 (2H, d), 3.38 (2H, dr), 3.16 (2H, d), 2.48 (1H, m),2.08 (2H, d), 1.54 (2M, dq); m/e 355 (M+H)⁺ ; calculated for C₂₀ H₂₂ N₂_(O) ₄. HCl.1.5H₂ O: C, 57.4; H, 6.1; N, 6.7. found: C, 57.3; H, 6.1; N,6.4%.

EXAMPLE 114 Methyl 4- 2-4-(4-pyridyl)piperazin-1-yl!-2,2-dimethyl-acetyl!phenoxyacetate.

Methyl 4-(2,2-dimethylbromoacetyl)phenoxyacetate (1.58 g) was added to astirred solution of 1-(4-pyridyl)piperazine (1.63 g) in acetonitrile (40ml). After 34 days, the solid formed was removed by filtration and thefiltrate evaporated to give an oil. Purification by flash chromatographyon silica, eluting with 0.5 to 4.0% v/v methanol/dichloromethane gavethe title compound, 240 mg, as a white foam: NMR (d₆ DMSO) δ 8.49 (2H,d), 8.12 (2H, d), 6.96 (2H, d), 6.77 (2H, d), 4.87 (2H, s), 3.69 (3H,s), 3.28 (4H, t), 2.58 (4H, t), 1.25 (6H, s); m/e 398 (M+H)⁺ ;calculated for C₂₂ H₂₇ N₃ O₄.0.25H₂ O: C, 65.7; H, 6.8; N, 10.4. found:C, 65.3; H, 6.9; N, 10.4%.

The necessary starting material was prepared as follows:

(i) Following the method of Example 67 step, (i) but starting from4-(2,2-dimethylacetyl)phenol and only stirring for 18 hours instead of 2days, there was obtained methyl 4-(2,2-dimethylacetyl)-phenoxyacetate,in 90% yield, as an off-white crystalline solid: m.p. 45°-46° C.; NMR(d₆ DMSO) δ 7.92 (2H, d), 7.02 (2H, d), 4.90 (2H, s), 3.71 (3H, s), 3.60(1H, m), 1.09 (6H, d).

(ii) Bromine (2.09 ml) was added dropwise over ten minutes to a stirredsolution of the product of step (i) above (9.44 g) in carbontetrachloride (200 ml). The solution was stirred for 16 hours, then thesolvent was evaporated in vacuo to give an orange oil. A solution ofthis oil, in a small volume of dichloromethane, was filtered throughsilica and the clear filtrate, on evaporation, gave methyl4-(2-bromo-2,2-dimethylacetyl)phenoxyacetate, 11.3 g, as a whitecrystalline solid: m.p. 46°-50° C.; NMR (d₆ DMSO) δ 8.09 (2H, d), 7.05(2H, d), 4.92 (2H, s), 3.72 (3H, s), 2.0(6H, s).

EXAMPLE 115 4- 2-4-(4-pyridyl)piperazin-1yl-!-2,2-dimethylacetyl!-phenoxyacetic acid.

Following the method of Example 2 but starting from the product ofExample 114 and stirring for 16 hours instead of 2 hours, the titlecompound was obtained in 76% yield, as a white crystalline solid: m.p.278°-279° C.; NMR (D₂ O) δ 8.72 (2H, d), 8.20 (2H, d), 7.16 (4H, d),4.76 (2H, s), 3.80 (4H, bt), 2.91 (4H, bt), 1.55 (6H, s); m/e 406(M+Na)⁺, 384 (M+H)⁺ ; calculated for C₂₁ H₂₅ N₃ O₄.0.5NaCl: C, 61.1; H,6.1; N, 10.2. found: C, 60.8; H, 5.9; N, 10.0%.

EXAMPLE 116 RS Methyl 4- 3-4-(4-pyridyl)piperazin-1-yl!-2-methyl-propanoyl!phenoxyacetate

A stirred mixture of methyl 4-(2,2-dimethylbromoacetyl)-phenoxyacetate(3.15 g), and 1-(4-pyridyl)piperazine (3.26 g) in acetonitrile (200 ml)was heated at reflux temperature for 4 days. The solvent was removed invacuo and the residue partioned between dichloromethane/water. Theorganic phase was dried (MgSO₄), evaporated and then purified by flashchromatography on silica, eluting with 2 to 5% v/vmethanol/dichloromethane. Further purification by flash chromatographyon neutral alumina, eluting with dichloromethane, gave the titlecompound, 350 mg, as a clear oil: NMR (d₆ DMSO) δ 8.12 (2H, d), 7.98(2H, d), 7.04 (2H, d), 6.75 (2H, d), 4.9 (2H, s), 3.86 (1H,m), 3.71 (3H,s), 3.19 (4H, t), 2.70 (1H, q), 2.49 (DMSO+4H), 2.36 (1H, q), 1.09 (3H,s), trace of dichloromethane; m/e 398 (M+H)⁺ ; calculated for C₂₂ H₂₇ N₃O₄.0.1 CH₂ Cl₂ : C, 65.3; H, 6.7; N, 10.3. found: C, 65.1; H, 6.9; N,10.1%.

EXAMPLE 117 Methyl 4- 4-4-(4-pyridyl)piperazin-1-yl!methylphenyl!-butyrate.

1-(4-Pyridyl)piperazine (1.63 g) was dissolved in warm acetonitrile (25ml), the solution cooled to 30° C. and with stirring, a solution ofmethyl 4-(4-bromomethylphenyl)butyrate in acetonitrile (5 ml) added.After 30 minutes the resulting precipitate was removed by filtration andthe filtrate concentrated in vacuo to give a yellow oil. Purification byflash chromatography on silica, eluting with 0 to 4% v/vmethanol/dichloromethane gave a solid. Trituration with ether andremoval of the insoluble solid gave a clear solution. Concentration ofthis solution gave the title compound, 0.90 g, as a white fluffy solid:m.p. 126°-127° C.; NMR (d₆ DMSO) δ 8.14 (2H, d), 7.24 (2H, d), 7.14 (2H,d), 6.77 (2H, d), 3.59 (3H, s), 3.48 (2H, s), 3.30 (4H, t), 2.59 (2H,t), 2.47 (4H, t), 2.32 (2H, t), 1.63 (2H, m); m/e 354 (M+H)⁺ ;calculated for C₂₁ H₂₇ N₃ O₂.0.25H₂ O: C, 70.4; H, 7.7; N, 11.7. found:C, 70.6; H, 7.6; N, 11.7%.

EXAMPLE 118 Methyl 5- 4-4-(4-pyridyl)piperazin-1-yl!methylphenyl!-pentanoate.

A mixture of methyl 5-(4-bromomethylphenyl)pentanoate and5-(2-bromomethylphenyl)pentanoate, 70:30 w/w by NMR, prepared accordingto the method for the starting material in Example 117 (2.14 g) wasreacted in a similar manner to Example 117. The crude mixture of esterswas purified by flash chromatography on silica, eluting with 0-5% v/vmethanol/dichloromethane. Evaporation of the appropriate fractions gavethe title compound, 605 mg, as a waxy solid: m.p. 53°-54° C.; NMR (d₆DMSO) δ 8.13 (2H, d), 7.23 (2H, d), 7.14 (2H, d), 6.79 (2H, d), 3.58(3H, s), 3.47 (2H, s), 3.30 (4H, t+H₂ O), 2.57 (2H, t) 2.46 (4H, t),2.32 (2H, t), 1.56 (4H, m); m/e 368 (M+H)⁺ ; calculated for C₂₂ H₂₉ N₃O₂.0.5H₂ O: C, 70.1; H, 8.0; N, 11.2. found: C, 70.3; H, 8.2; N, 11.0%.

EXAMPLE 119 4- 4- 4-(4-pyridyl)piperazin-1-yl!methylphenyl!butyric acid,dihydrochloride.

Following the method of Example 71 but starting from the product ofExample 118 and heating at 100° C. for 4 hours instead of 1.5 hours thetitle compound was prepared in 88% yield: m.p. 236°-238° C.; NMR (D₂ O)δ 8.40 (2H, d), 7.66 (2H, d), 7.6.1 (2H, d), 7.36 (2H, d), 4.61 (2H, s),4.19 (4H, b), 3.69 (4H, b), 2.94 (2H, t), 2.61 (2H, t), 2.15 (2H, m);m/e 340 (H+H)⁺ ; calculated for C₂₀ H₂₅ N₃ O₂. 2HCl. 0.5H₂ O: C, 57.0;H, 6.6; N, 10.0. found: C, 57.2; H, 6.9; N, 9.8%.

EXAMPLE 120 Mixture of 5- 4-4-(4-pyridyl)piperazin-1-yl!-methylphenyl!pentanoic acid and 5- 2-4-(4-pyridyl)piperazin-1-yl!-methylphenyl!pentanoic acid,dihydrochloride (4:1).

Following the method of Example 119, but starting from the crude mixtureof esters in Example 118, there was obtained the title mixture ofcompounds in 59% yield, as a white solid: NMR (D₂ O) δ 8.38 (2H, d),7.62 (4H, m), 7.35 (2H, d), 4.70 (0.4H, s), 4.61 (1.6H, s), 4.18 (4H,b), 3.68 (4H, b), 2.98 (0.4H, t), 2.91 (1.6H, t), 2.59 (2H, t), 1.82(4H, m); m/e 354 (M+H)⁺ ; calculated for C₂₁ H₂₇ N₃ O₂.2HCl.0.5H₂ O: C,57.9; H, 6.9; N, 9.7. found: C, 59.6; H, 7.2; N, 9.4%.

EXAMPLE 121 Ethyl 6- 4-(4-pyridylamino)phenoxy!hexanoate.

Trifluoroacetic acid (3 ml) was added to a stirred solution of ethyl 6-4- N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino!-phenoxy!hexanoate(260 mg) dissolved in dichloromethane (3 ml). After 18 hours thesolvents were removed in vacuo and the residual gum dissolved indichloromethane. This solution was treated with a saturated solution ofsodium hydrogen carbonate. The organic phase was washed with water,dried and evaporated. Trituration of the residue with hexane gave thetitle compound, 120 mg, as a white solid: m.p. 104°-106° C.; NMR (CDCl₃)δ 8.22 (2H, d), 7.12 (2H, d), 6.90 (2H, d), 6.64 (2H, dd), 5.82 (1H, s),4.13 (2H, q), 3.97 (2H, t), 2.34 (2H, t), 1.80 (2H, m), 1.70 (2H, m),1.53 (2H, m), 1.27 (3H, t); m/e 329 (M+H)⁺ ; calculated for C₁₉ H₂₄ N₂O₃. 0.25H₂ O:C, 68.6; H, 7.4; N, 8.4. found: C, 68.8; H, 7.3; N, 8.2%.

The necessary starting material was prepared as follows:

(i) A stirred mixture of 4-chloropyridine hydrochloride (2 g) and4-methoxyaniline (4.9 g) was heated at 140° C. for 5 hours. Aftercooling the residue was dissolved in dichloromethane (250 ml), thesolution extracted with water (2×100 ml). The aqueous extracts weretreated with sodium hydroxide solution and then extracted with ethylacetate (4×100 ml). The combined organic extracts were washed withwater, and saturated sodium chloride solution, then dried and thesolvent evaporated. Purification by flash chromatography on silica,eluting with 10% v/v methanol/dichloromethane gave4-(4-pyridylamino)-methoxybenzene, 2 g, as a fawn solid: m.p. 159°-160°C.; NMR (d₆ DMSO) δ8.47 (1H, s), 8.09 (2H, d), 7.10 (2H, d), 6.92 (2H,d), 6.70 (2H, dd), 3.73 (3H, s); m/e 201 (M+H)⁺ ; calculated for C₁₂ H₁₂N₂ O₃ : C, 72.0; H, 6.0; N, 14.0. found: C, 71.4; H, 6.1; N, 13.8%.

(ii) A mixture of the product from step (i) above (2.0 g) and 48% w/vhydrobromic acid (30 ml) was heated at 140° C. for 4 hours. The cooledsolution was neutralised with 0.880 ammonia solution and then extractedfour times with ethyl acetate. The combined organic extracts were washedwith water and saturated sodium chloride solution, then dried (MgSO₄)and evaporated. Purification by flash chromatography on silica, elutingwith 10 to 20% v/v methanol/dichloromethane gave4-(4-pyridylmaino)phenol, 0.78 g as an off-white solid: m.p. 246°-248°C.; NMR (CDCl₃ +d6DMSO) δ 8.92 (1H, b), 8.09 (2H, d), 7.31 (1H, s), 7.00(2H, d), 6.79 (2H, d), 6.67 (2H, dd); m/e 187 (M+H)⁺

(iii) A mixture of the product from step (ii) above (0.78 g),di-tertiary-butyl dicarbonate (0.91 g), triethylamine (0.59 ml),1,2-dimethoxymethane (20 ml) and water (10 ml) was stirred for 18 hours.The solvents were removed in vacuo and the residue partitioned betweenethyl acetate and water. The aqueous phase was extracted two times withfurther ethyl acetate and the combined organic extracts washed withwater and brine, dried (MgSO₄) and evaporated to a small volume whencrystallisation occurred. Collection by filtration gave 4-N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino!phenol, 1.07 g as a whitecrystalline solid: m.p. 192°-194° C. (dec); NMR (CDCl₃) δ 8.28 (2H, dd),7.18 (4H, s), 6.76 (2H, dd), 6.03 (1H, bs), 1.57 (9H, s); m/e 287(M+H)⁺.

(iv) Sodium hydride (50% w/w dispersion in mineral oil, 55 mg) was addedunder argon to a stirred solution of the product from step (iii) above(300 mg) in dry DMF (5 ml). After five minutes, ethyl 6-bromohexanoate(0.20 ml) was added and the mixture stirred for 16 hours. The DMF wasevaporated in vacuo and the residue partitioned between dichloromethaneand water. The aqueous phase was extracted with further dichloromethane.The combined organic extracts were washed with water then dried, andevaporated. The residue was purified by chromatography on alumina,eluting with dichloromethane and then 1% v/v methanol/dichloromethane.Evaporation of the appropriate fractions gave ethyl 6- 4-N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino!phenoxy!hexanoate, 260mg, as a yellow gum: NMR (CDCl₃) δ 8.40 (2H, dd), 7.16 (2H, dd), 7.07(2H, m), 6.90 (2H, m), 4.13 (2H, q), 3.98 (2H, t), 2.34 (2H, t), 1.78(4H, m), 1.57 (2H, m), 1.44 (9H, s), 1.26 (3H, t); m/e 429 (M+H)⁺.

EXAMPLE 122 6- 4-(4-pyridylamino)phenoxy!hexanoic acid hydrochloride

Following the method of Example 71, but starting from the product ofExample 121 and heating at 100° C. for 16 hours instead of 1.5 hours,the title compound was obtained in 80% yield as a freeze-dried solid:NMR (d₆ DMSO) δ 13.63 (1H, b), 11.95 (1H, b), 10.49 (1H, s), 8.21 (2H,d), 7.26 (2H, d), 6.98 (4H, m), 4.00 (2H, t), 2.23 (2H, t), 1.70 (2H,m), 1.55 (2H, m), 1.45 (2H, m), m/e 301 (M+H)⁺ ; calculated for C₁₇ H₂₀N₂ O₂. HCl. 1.25H₂ O: C, 56.8; H, 6.6; N, 7.8. found: C, 56.8; H, 6.6;N, 7.4%.

EXAMPLE 123 N- 4- (4-pyridyl)piperazin-1-yl!benzoyl!-N-methylglycine,trifluoroacetate

To a solution of ethyl N- 4-(4-pyridyl)piperazin-1-yl!-benzoyl!-N-methylglycinate (78 mg) inmethanol (2 ml) was added sodium hydroxide solution (1N, 0.4 ml) and theresultant mixture was stored at room temperature for 1 hour. The pH ofthe reaction mixture was adjusted to 2 by addition of 2N HCl (aq)(0.45-0.5 ml) and the resultant solution was purified by preparativerp-hplc on a DYNAMAX C-18, 60A 83-201-C! column using anacetonitrile/water mobile phase containing 0.1% trifluoroacetic acid, togive, after lyophilisation, the title compound (46 mg) as a glass: NMR(d₆ -DMSO) δ 2.98 (3H, s), 3.45 (4H, m), 3.86 (4H, m), 4.07 (2H, s),6.97 (2H, d), 7.23 (2H, d), 7.31 (2H, m), 8.27 (2H, d); m/Z 355 (M+H)⁺ ;calculated for C₁₉ H₂₂ N₄ O₃. 1.0 CF₃ CO₂ H. 1.25 H₂ O: C, 51.4%; H,5.24%; N, 11.4%; found: C, 51.2%; H, 4.9%; N, 11.2%.

The necessary starting material was prepared as follows:

(i) To a stirred mixture of 4- (4-pyridyl)piperazin-1-yl!benzoic acid(prepared as in Example 30(i)) (311 mg), HOBt.H₂ O (170 mg) and HBTU(416 mg) in DMF (5 ml) at 0°-5° C. under argon was addeddiisopropylethylamine (0.75 ml). The ice-bath was removed and thereaction mixture was stirred at room temperature for 15 minutes beforesolid sarcosine, ethyl ester hydrochloride (154 mg) was added. Thereaction mixture was stirred at room temperature under argon overnightthen diluted with dichloromethane (30 ml) and water (30 ml). The organiclayer was separated and the aqueous layer was re-extracted withdichloromethane (30 ml). The combined organic extracts were washed withwater, saturated sodium bicarbonate solution, water, dried (MgSO₄) andevaporated. The residue was purified by filtration through a short bedof activated (grade II) alumina by elution with ethyl acetate/methanol,5:1, to give ethyl N-(4-(4-pyridyl)piperazin-1-yl!benzoyl)-N-methylglycinate (92 mg) as anamorphous solid: NMR (d₆ -DMSO+CD₃ CO₂ D) δ 1.18 (3H, t), 2.98 (3H, s),3.44 (4H, m), 3.79 (4H, m), 4.11 (4H, m), 6.94 (2H, d), 7.12 (2H, d),7.31 (2H, br, d), 8.19 (2H, d); m/Z 383 (M+H)⁺.

EXAMPLE 124 N- 4- (4-pyridyl)piperazin-1-yl!benzoyl!-L-phenylalanine,methyl ester

In a similar manner to Example 123 (i), 4-(4-pyridyl)piperazin-1-yl!benzoic acid (311 mg), p-toluene sulphonicacid, monohydrate (418 mg), HOBt.H₂ O (170 mg), HBTU (416 mg), DMF (5ml), diisopropylethylamine (1.13 ml) and L-phenylalanine, methyl esterhydrochloride (216 mg) gave, after filtration through a bed of neutralalumina and elution with ethyl acetate/methanol, 6:1, the title compoundas a white crystalline solid (336 mg): m.p. 139°-143.5° C.; NMR (CDCl₃)δ 3.26 (2H, m), 3.50 (8H, m), 3.76 (3H, s), 5.09 (1H, m), 6.46 (1H, d),6.70 (2H, m), 6.90 (2H, d), 7.13 (2H, m), 7.28 (3H, m), 7.68 (2H, d),8.31 (2H, m); m/z 445 (M+H)⁺ ; calculated for C₂₆ H₂₈ N₄ O₃. 1.0 H₂ O:C, 67.5%; H, 6.54%; N, 12.1%; found: C, 67.6%; H, 6.4%; 12.1%.

EXAMPLE 125 N- 4- (4-pyridyl)piperazin-1-yl!benzoyl!-L-phenylalanine

To a solution of the product of Example 124 (100 mg) in methanol (2.2ml) was added sodium hydroxide solution (1N, 0.44 ml). The resultantmixture was stored at room temperature with occasional swirling for 2.5hr, then the pH was adjusted to 5 by addition of 2N HCl (aq) (0.22 ml)and 50% aqueous acetic acid (3 drops). The mixture was filtered andevaporated to dryness. The residue was crystallised from hot watercontaining a trace of methanol to give the title compound as a paleyellow crystalline solid (47 mg): NMR (d₆ -DMSO+CD₃ CO₂ D) δ 3.05 (1H,m), 3.15 (1H, m), 3.45 (4H, m), 3.77 (4H, 4.58 (1H, m), 6.90 (2H, d),7.12 (2H, d), 7.22 (5H, m), 7,70 (2H, d), 8.19 (2H, d); m/Z 431 (M+H)⁺ ;calculated for C₂₅ H₂₆ N₄ O₃. 0.75 H₂ O: C, 67.6%; H, 6.24%; N, 12.6%;found: C, 67.6%; H, 6.0%; N, 12.5%.

EXAMPLE 126 (S)-3- N-2-phenethyl!carboxamido!-3-!4-!-4-(4-pyridyl)piperazin-1-yl!!benzamidopropionicacid

To a stirred suspension of benzyl (S)-3- N- 2-phenethyl!-carboxamido!-3-4- 4-(4-pyridyl)piperazin-1-yl!!benzamidopropionate (120 mg) in methanol(3 ml) was added sodium hydroxide solution (1N, 0.5 ml). Within 15minutes all the solids had dissolved, and the reaction mixture wasstirred at room temperature for a further 2 hr. The pH was then adjustedto 5 by addition of 2N HCl (aq) (0.25 ml) and 50% aqueous acetic acid (3drops). The mixture was filtered and evaporated to dryness. The residuewas crystallised from hot water containing a trace of methanol to givethe title compound as a pale yellow crystalline solid (66 mg): NMR (d₆-DMSO+CD₃ CO₂ D) δ 2.70 (4H, m), 3.30 (2H, t), 3.56 (4H, m), 3.85 (4H,m), 4.73 (1H, m), 6.99 (2H, d), 7.20 (7H, m), 7.80 (2H, d), 8.25 (2H,d); m/Z 502 (M+H)⁺ ; calculated for C₂₈ H₃₁ N₅ O₄. 1.25 H₂ O: C, 64.2%;H, 6.44%; N, 13.4%; found: C, 64.2%; H, 6.4%; N, 13.6%.

The necessary starting material was prepared as follows:

i) Boc-L-aspartic acid, 2-phenethylamide, β-benzyl ester (preparationdescribed in Samanen, J. et al (1991), J. Med. Chem. 34, 3114-25) (2 g)was dissolved in a mixture containing dichloromethane (10 ml) andtrifluoroacetic acid (10 ml). The resultant pale yellow solution wasstored at room temperature for 2 hr after which time the mixture wasevaporated to dryness. The oily product was dissolved in dry ether andre-evaporated. This procedure was repeated twice more to give a viscousoily residue containing the trifluoroacetate salt of L-aspartic acid,2-phenethylamide, β-benzyl ester (2.07 g) which was used without furtherpurification.

ii) In a similar manner to Example 123 (i), 4-(4-pyridyl)piperazin-1-yl!benzoic acid (311 mg), p-toluene sulphonicacid, monohydrate (627 mg), HOBt.H₂ O (170 mg), HBTU (416 mg), DMF (15ml), diisopropylethylamine (1.5 ml) and L-aspartic acid,2-phenethylamide, β-benzyl ester (440 mg) gave, after purification byflash chromatography on silica, eluting solvent, ethyl acetate/methanol,4:1 to 2:1, benzyl (S)-3-(N- 2-phenethyl!-carboxamido)-3- 4-4-(4-pyridyl)piperazin-1-yl!!benzamidopropionate (268 mg) as a whitecrystalline solid: NMR (d₆ -DMSO) δ 2.70 (2H, t), 2.76 (1H, m), 2.88(1H, m), 3.25 (2H, m), 3.44 (4H, m), 3.50 (4H, m), 4.84 (1H, m), 5.08(2H, s), 6.89 (2H, d), 7.02 (2H, d), 7.20 (5H, m), 7.31 (5H, m), 7.78(2H, d), 7.90 (1H, t), 8.20 (2H, d), 8.36 (1H, d); m/Z 592 (M+H)⁺ ;calculated for C₃₅ H₃₇ N₅ O₄, 0.25 H₂ O: C, 70.5%; H, 6.34%; N, 11.7%;found: C, 70.5%; H, 6.3%; N, 11.7%.

EXAMPLE 127 (R)-3- N- 2-phenethyl!carboxamido!-3- 4-4-(4-pyridyl)piperazin-1-yl!!benzamidopropionic acid

Following the method of Example 126, but starting from benzyl (R)-Z- N-2-phenethyl!carboxamido!-3- 4-4-(4-pyridyl)-piperazin-1-yl!!benzamidopropionate instead of thecorresponding (S)-isomer, the title compound was obtained as a paleyellow crystalline solid in 33% yield: NMR (d₆ -DMSO+CD₃ CO₂ D) δ 2.71(4H, m), 3.29 (2H, t), 3.53 (4H, m), 3.83 (4H, m), 4.72 (1H, m), 6.99(2H, d), 7.17 (7H, m), 7.77 (2H, d), 8.24 (2H, d); m/Z 502 (M+H)⁺ ;calculated for C₂₈ H₃₁ N₅ O₄. 1.25 H₂ O: C, 64.2%; H, 6.44%; N, 13.4%;found: C, 64.2%; H, 6.4%; N, 13.3%.

The necessary starting material was prepared as follows:

i) Boc-D-aspartic acid, 2-phenethylamide, β-benzyl ester (preparationdescribed in Rodriguez, M. et al (1989), J. Med. Chem. 32, 522-8) (1 g)was dissolved in acetonitrile (5 ml) with gentle warming, then cooled toroom temperature before excess ethereal HCl (5 ml) was added. Thereaction mixture was stored at room temperature overnight thenevaporated to dryness. The pale yellow oily residue was triturated withdry ether and re-evaporated. This procedure was repeated twice more togive a hygroscopic oily residue containing the hydrochloride salt ofD-aspartic acid, 2-phenethylamide, β-benzyl ester (0.55 g)which was usedwithout further purification.

ii) In a similar manner to Example 30 the hydrochloride salt ofD-aspartic acid, 2-phenethylamide, β-benzyl ester (363 mg), 4-(4-pyridyl)piperazin-1-yl!benzoyl chloride (377 mg),diisopropylethylamine (0.87 ml) and DMF (5 ml) gave benzyl (R)-3- N-2-phenethyl!carboxamido!-3-4-!-4-(4-pyridyl)-piperazin-1-yl!!benzamidopropionate (510 mg) as anoff-white, amorphous solid: m/Z 592 (H+H)⁺.

EXAMPLE 128 4-oxo-4- 4-4-(4-pyridyl)piperazin-1-yl!-phenyl!-aminobutyric acid

To a solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (100 mg) inDMF (8 ml) was added succinic anhydride (79 mg). The reaction mixturewas stirred at room temperature for 2.5 hr and a precipitate wascollected, washed with DMF and ethanol, then dried to give the titlecompound (106 mg) as a beige-coloured solid: m.p. 263°-264° C.; NMR (d₆-DMSO+CF₃ CO₂ H) δ 2.68 (4H, m), 3.80 (4H, m), 4.19 (4H, m), 7.20 (2H,d), 7.56 (2H, d), 7.82 (2H, d), 8.21 (2H, d), 9.62 (1H, s); m/Z 355(M+H)⁺ ; calculated for C₁₉ H₂₂ N₄ O₃. 0.4 H₂ O: C, 63.1%; H, 6.36%; N,15.5%; found: C, 63.1%; H, 6.4%; N, 15.7%.

The necessary starting material was prepared as follows:

(i) To an intimate mixture of 4- (4-pyridyl)piperazin-1-yl!-benzoic acid(Example 30(i)) (500 mg) and hydroxylamine hydrochloride (13.5 mg) wasadded polyphosphoric acid (16 g). The resultant mixture was heated to160° C. and maintained at that temperature with stirring for 30 min. Themixture was then allowed to cool to approximately 100° C. before crushedice, followed by 15% potassium hydroxide solution to give a pH 11 ofwere added. The suspension was allowed to cool to room temperature andthe precipitate was collected, washed with water and air-dried to give1-(4-aminophenyl)-4-(4-pyridyl)piperazine (159 mg) as a light brownsolid: m.p. 204°-208° C.; NMR (d₆ -DMSO) δ 3.00 (4H, m) 3.41 (4H, m),4.65 (2H, br. s), 6.51 (2H, d), 6.73 (2H, m), 6.85 (2H, d), 8.18 (2H,d); m/Z 255 (H+H)⁺.

EXAMPLE 129 4- 4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid,hydrochloride salt

A mixture of the product from Example 26 (1.5 g) and methanol (80 ml)was heated to reflux with stirring, and solid pyridine hydrochloride(0.5 g) was added. Heating was stopped and ethyl acetate (10 ml) wasadded. The reaction mixture was evaporated until a slight turbidity wasobserved. On further cooling, a precipitate formed which was collected,washed with ethyl acetate and dried to give the title compound (1.33 g)as a beige solid: m.p.>240° C. (dec); NMR (d₆ -DMSO) δ 1.90 (2H, m),2.36 (2H, t), 3.17 (4H, m), 3.83 (4H, m), 3.91 (2H, t), 6.89 (4H, q),7.26 (2H, d), 8.25 (2H, d), 12.1 (1H, br), 13.75 (1H, br); m/Z 342(M+H)⁺ ; calculated for C₁₉ H₂₃ N₃ O₃. 1.0 HCl: C, 60.4%; H, 6.4%; N,11.1%; found: C, 60.0%; H, 6.4%, N, 10.8%.

EXAMPLE 130 N-2-methoxyethyl-4- 4-4-(4-pyridyl)piperazin-1-yl!-phenoxy!butyramide, trifluoroacetate

A solution of methoxyethylamine (0.9 ml) in dry dichloromethane (5 ml)was added dropwise to a stirred solution of trimethylaluminium, 2M intoluene (5 ml) at 5°-10° C. under argon. On completion of the addition,the ice-bath was removed and the reaction mixture was stirred at roomtemperature for 1 hr before a solution of the product of Example 25(0.62 g) in dichloromethane (5 ml) was added dropwise. The reactionmixture was heated to reflux under argon and stirred at reflux for 2 hr.The reaction mixture was then cooled to room temperature and dilutedwith dichloromethane (20 ml). A solution of methanol/dichloromethane,1:1 (3 ml) was then added dropwise with stirring. The reaction mixturewas further diluted with dichloromethane (10 ml), methanol, (3 ml) andwater (5 ml). The organic layer was separated, dried (Na₂ SO₄) andevaporated to dryness. The residue was purified by preparative rp-hplcon a DYNAMAX C-18, 60A 83-201-C! column using an acetonitrile/watermobile phase containing 0.1% trifluoroacetic acid, to give, afterlyophilisation, the title compound (56 mg) as an off-white solid: NMR(d₆ -DMSO) δ 1.89 (2H, m), 2.22 (2H, t), 3.18 (6H, m), 3.23 (3H, s),3.32 (2H, t), 3.85 (6H, m), 6.90 (4H, q), 7.28 (2H, d), 7.88 (1H, br.t), 8.25 (2H, d); m/Z 399 (M H)⁺ ; calculated for C₂₂ H₃₀ N₄ O₃. 1.7 CF₃CO₂ H: C; 51.5%; H, 5.4%; N, 9.5%; found: C, 51.4%; H, 5.6%; N, 9.3%.

EXAMPLE 131 4- 2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!-phenoxyacetic acidmonohydrochloride

A solution of methyl 4- 2-(piperazin-2-one-1-yl)acetyl!-phenoxyacetate(0.347 g), 4-chloropyridine hydrochloride (0.19 g) and triethylamine(0.178 g) in water (8 ml) and dioxan (1 ml) was heated on a steam bathfor 2 hours and then evaporated to dryness. The residue was trituratedwith water (2 ml) and filtered. The solid thus obtained wasrecrystallised from water to give the title compound (0.187 g), m.p.275°-277° C.; NMR(d₆ DMSO δ 8.33(2H,d), 8.0(2H,d), 7.21(2H,d),7.1(2H,d), 4.97(2H,s), 4.81(2H,s), 3.94(2H,m), 3.59(2H,m); m/e 370(H+H)⁺; calculated for C₁₉ H₂₀ N₃ O₅ Cl. 0.75 H₂ O: C, 54.4; H, 5.0; N, 10.0.Found: C, 54.5; H, 5.3; N, 9.5%.

The necessary starting material was made as follows:

(i) To a vigorously stirred mixture of piperazinone (3.23 g), potassiumcarbonate (4.46 g) in water (15 ml) and tert butanol (15 ml) at roomtemperature, was added portionwise over 5 minutes, di tert butyldicarbonate (7.75 g). The mixture was stirred for 2 hours. Ethyl acetate(20 ml) was added to extract the solid thus formed and the organic layerseparated, filtered through phase separating paper and evaporated. Thesolid residue was recrystallised from ethyl acetate to give 4-tertbutoxycarbonylpiperazin-2-one (5.31 g), m.p. 157°-159° C.; NMR(d₆ DMSO)δ 8.0(1H,broad), 3.81(2H,s), 3.45(2H,t), 3.17(2H,m), 1.4(9H,s); m/e 207(H+H)⁺.

(ii) To a stirred suspension of the product of step i) (0.5 g) in dryDMF (3 ml) under an argon atmosphere, was added sodium hydride (60%dispersion in mineral oil, 0.1 g). After 1 hour at room temperature,methyl 4-bromoacetylphenoxyacetate (0.72 g) was added and the solutionstirred for 11/2 hours. The mixture resulting was partitioned betweenwater and ethyl acetate. The organic layer was separated, washed withwater and filtered through phase separating paper. Evaporation of thesolvent gave an oil which was purified by flash column chromatography,the product being eluted with 1/1 v:v ethyl acetate/hexane to givemethyl 4-(2-(4-tert-butoxycarbonyl)piperazin-2-one-1-yl!acetyl)phenoxyacetate as asolid (0.32 g), m.p. 81°-82° C.; NMR(CDCl₃) δ 7.97(2H,m), 6.98(2H,m),4.83(2H,s), 4.71(2H,s), 4.18(2H,s), 3.81(3H,s), 3.72(2H,t), 3.42(2H,t),1.47(9H,s).

(iii) A solution of the product from step (ii) (2.2 g) in TFA (10 ml)was kept at room temperature for 1 hour and then evaporated to dryness.The residue was partitioned between ethyl acetate and aqueous sodiumcarbonate. The organic layer was filtered through phase separating paperand solvent evaporated. The residue was triturated with ethyl acetate togive a solid, m.p. 128°-132° C. NMR(d₆ DMSO) δ 7.95(2H,d), 7.06(2H,d),4.9(2H,s), 3.7(3H,s), 3.3(2H,m), 2.9(2H,m).

EXAMPLE 132 RS 3-Methyl-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-butyric acid, trifluoroacetate

To a stirred suspension of 4- 4-(4-pyridyl)piperazin-1-yl!phenol (1.02g) in dry DMF (10 ml) was added sodium hydride (60% dispersion inmineral oil, 0.16 g) and the mixture stirred for 1 hour at roomtemperature. To the resulting solution was addedethyl-4-bromo-3-methylbutyrate and the mixture stirred for 16 hours.Solvent was evaporated and the residue partitioned between water anddichloromethane. Insoluble material was removed by centrifugation. Theorganic layer was filtered through phase separating paper (Whatman IPS)and the residue was purified by flash chromatography on silica gel byelution with methanol/dichloromethane/concentrated ammonia (50/950/5) togive ethyl 3-methyl-4- 4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate(0.27 g) which was hydrolysed in methanol (3 ml) and aqueous sodiumhydroxide (1N, 2 ml) for 2 hours at room temperature. The solution wasevaporated and the residue purified by reverse phase h.p.l.c(water/acetonitrile/0.1% TFA gradient) to give a glass whichcrystallised on trituration with ether to give the title compound (0.08g): m.p. 169°-171° C.; NMR(d₆ DMSO) δ 13.45(1H,broad), 2.07(1H,broad)8.27(2H,d), 7.28(2H,d), 6.9(4H,m), 3.80(6H,m), 3.16(4H,t), 2.45(1H,m),2.37(1H,m), 2.12(1H,m), 1.0(3H,d); m/e 356(M+H)⁺ ; calculated for C₂₂H₂₅ N₃ O₄ F₃. 0.5 H₂ O: C, 55.2; H, 5.6; N, 8.9. Found: C, 55.3; H, 5.6;N, 8.7%.

EXAMPLE 133 RS-4- 4- 4-4-(4-pyridyl-piperazin-1-yl!phenoxy!-3-vinyl!butyric acid, sodium salt

A solution of RS methyl 4- 4-4-(4-pyridyl)piperazin-1-yl!-phenoxy!-3-vinylbutyrate (0.29 g) in 1Nsodium hydroxide solution (2.3 ml) and methanol (5 ml) was kept at roomtemperature for 4 hours. The solution was evaporated and water (2 ml)added to the solid residue. The solid thus obtained was filtered andwashed with acetone and ether to give the title compound (0.042 g): m.p.293°-295° C.; NMR (d₆ -DMSO) δ 8.18(2H,d), 6.9(6H,m), 5.88(1H,m),4.96(2H,m), 4.0(1H,m), 3.77(1H,t), 3.41(2H,m), 3.10(2H,m), 2.84(1H,m),1.98(2H,d), m/e 470(M+H)⁺ ; calculated for C₂₁ H₂₄ N₃ O₃ Na. H₂ O: C,61.9; H, 6 4; N 10.3. Found: C, 62.1; H, 6.4; N, 10.5%.

The necessary starting material was made as follows:

(i) A solution of RS 3-vinylbutyrolactone (3.5 g) and sodium acetate(2.56 g) in methanol (30 ml) was kept for 20 hours. Solvent wasevaporated and the residue was partitioned between water and ether. Theaqueous layer was extracted twice more with ether and the extractscombined, filtered through phase separating paper and evaporated. Theresidue was purified by filtration chromatography on silica gel (Merck7736) starting with 1/9 ethyl acetate/hexane and progressing to 4/6ethyl acetate/hexane as eluent to give methyl 4-hydroxy-3-vinylbutyrateas an oil; NMR(CDCl₃) δ 5.73(1H,m), 5.15(2H,m), 3.68(3H,s), 3.60(2H,t),2.76(1H,m), 2.48(2H,m), 1.69(1H,t); m/e 145(M+H)⁺.

(ii) To a stirred suspension of 4- 4-(4-pyridyl)piperazin-1-yl!phenol(1.98 g) in dichloromethane (30 ml) at 15° C. was addedtriphenylphosphine (2.04 g) followed by dropwise addition of diethylazodicarboxylate (1.35 g). The mixture was stirred until completesolution was obtained. Methyl-4-hydroxy-3-vinylbutyrate (1.12 g) wasadded dropwise and the mixture stirred for 4 hours. The solid which hadprecipitated during the reaction was the starting phenol and wasfiltered off. The filtrate was evaporated and the residue treated withethyl acetate (20 ml) and filtered. The filtrate was extracted with 2Nhydrochloric acid (2×10 ml) and the aqueous layer separated and basifiedwith 0.89 S.G. ammonium hydroxide. The precipitate was extracted twiceinto ethyl acetate and the combined extracts filtered through phaseseparating paper and evaporated. The residue was purified by flashchromatography on silica gel, eluting with methanol/dichloromethane/0.89S. G. ammonium hydroxide v:v:v 7.5/92.5/0.75 to give RS methyl 4- 4-4-(4-pyridyl)piperazin-1-yl!-phenoxy!-3-vinylbutyrate (0.29 g);NMR(CDCl₃) δ 8.3(2H,d), 6.88(4H,m), 6.70(2H,d), 5.85(1H,m), 5.20(2H,m),3.90(2H,m), 3.67(3H,s), 3.48(2H,m), 3.18(2H,m), 3.06(1H,m), 2.68(1H,m),2.47(1H,m), 1.80(1H,br); m/e 382 (M+H)⁺.

EXAMPLE 134 Ethyl 4- 2-allyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate

In a similar manner to Example 25 but starting from 2-allyl-4-4-(4-pyridyl)piperazin-1-yl!phenol, the title compound was prepared in50% yield as a solid, m.p. 53°-55° C. NMR(CDCl₃) δ 8.3(2H,d),6.83(1H,m), 6.79(2H,d), 6.71(2H,d.d), 6.0(1H,m), 5.1(2H,m), 4.15(2H,q),3.98(2H,t), 3.49(4H,m), 3.39(2H,d), 3.19(4H,m), 2.53(2H,t), 2.11(2H,q),1.76(3H,t), m/e 410(M+H)⁺ ; calculated for C₂₄ H₃₁ N₃ O₃.0.5 H₂ O: C,68.9; H, 7.7; N, 10.0. Found: C, 68.8; H, 7.7; N, 9.9%.

The necessary starting material was prepared as follows:

(i) Sodium hydride (60% dispersion in mineral oil, 0.4 g) was added to astirred suspension of 4- 4-(4-pyridyl)piperazin-1-yl!phenol (2.55 g) inDMF (25 ml) and the mixture stirred for 20 minutes at room temperature.Allyl chloride (0.756 g) was added dropwise and stirring continued for20 hours. Ice-water (75 ml) was added and the mixture extracted threetimes with ethyl acetate. The combined extracts were washed with waterand brine, dried (MgSO₄) and evaporated. The residue was triturated withhexane and filtered to give 4- 4-(4-pyridyl)piperazin-1-yl!phenol allylether (2.5 g) as a solid;

NMR(d₆ DMSO) δ 8.18(2H,dd), 6.8-7.0(6H,m), 5.92-6.13(1H,m),5.2-5.45(2H,m), 4.5(2H,m), 3.45(4H,m), 3.11(4H,m).

(ii) The product from step (i) (5 g) was heated under argon in gentlyrefluxing diphenyl ether (15 g) for 21/2 hours. The mixture was cooledto room temperature and ether (70 ml) was added. The solid material wasfiltered and purified by flash chromatography on silica gel, elutingwith methanol/dichloromethane (1/4 v/v) to give 2-allyl-4-4-(4-pyridyl)piperazin-1-yl!phenol (0.88 g) as a solid, m.p. 180°-182°C.; NMR (d₆ -DMSO) δ 8.88(1H,s), 8.19(2H,dd), 6.87(2H,dd), 6.7(3H,m),5.88-6.03(1H,m), 5.0(2H,m), 3.44(4H,t), 3.28(2H,d), 3.05(4H,t); m/e 296(M+H)⁺.

EXAMPLE 135 4- 2-allyl-4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyricacid

In a similar manner to Example 26, but starting from the product ofExample 134, the title compound was prepared as solid in 61% yield; m.p.209°-210° C. (dec); NMR (d₆ DMSO) δ 8.19(2H,d), 6.84(5H,m),5.82-6.08(1H,m), 4.92-5.12(2H,m), 3.91(2H,t), 3.44(4H, t), 3.3(2H,d),3.1(4H,t), 2.4(2H,t), 1.93(2H,t); m/e 382(M+H)⁺ ; calculated for C₂₂ H₂₇N₃ O₃ : C, 69.3; H, 7.13; N, 11.0. Found: C, 69.2; H, 7.3; N, 11.2%.

EXAMPLE 136 Ethyl 4- 2-n-propyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate

In a similar manner to Example 25, but starting from 2-n-propyl-4-4-(4-pyridyl)piperazin-1-yl!phenol, the title compound was prepared in24% yield as a solid, m.p. 65°-67° C.; NMR(CDCl₃) δ 8.29(1H,d),6.8(1H,d), 6.73(2H,d), 6.7(2H,d), 4.13(2H,q), 3.94(2H, t), 3.46(4H,t),3.18(4H,t), 2.52(4H,m), 2.09(2H,m), 1.54(2H,m), 1.24(3H,t), 0.94(3H,t);m/e 412(M+H)⁺.

The necessary starting material was prepared as follows:

The product from Example 134, step (ii) (0.74 g) in ethanol (25 ml) and1N hydrochloric acid (2.5 ml) was hydrogenated at room temperature andatmospheric pressure over 10% palladium charcoal (0.15 g) until uptakeof hydrogen was complete. Catalyst was removed by filtration throughdiatomaceous earth and the filtrate evaporated. The residue wastriturated with a mixture of ethyl acetate (25 ml) and saturated sodiumbicarbonate solution (25 ml) and the insoluble solid was filtered andwashed with water and ethyl acetate. The aqueous layer of the filtratewas extracted twice with dichloromethane and the combined organicextracts evaporated. The residue was combined with the ethylacetate-insoluble material and treated with boiling ethanol (40 ml),unsoluble material being removed by filtration. Evaportion of thefiltrate gave 2-n-propyl-4- 4-(4-pyridyl)piperazin-1-yl!phenol (0.7 g)as a solid NMR (d₆ DMSO) δ 8.84-8.68(1H,m), 8.18(2H,d), 6.82(2H,m),6.7(3H,m), 4.1(1H,m), 3.42(4H,t), 3.17(3H,s), 3.05(4H,t), 2.48(DMSO),1.55(2H,m), 0.89(3H,t).

EXAMPLE 137 4- 2-n-propyl-4-4-(4-pyridyl)piperazin-1-yl!-phenoxy!butyric acid

In a similar manner to Example 26, but starting from the product ofExample 136 was prepared the title compound in 64% yield; m.p. 207°-209°C. (from isopropanol); NMR(d₆ DMSO) δ 8.18(2H,d), 6.7-6.92(5H,m),3.91(2H,t), 3.45(4H,t), 3.10(4H,t), 2.5(DMSO), 2.4(2H,t), 1.91(2H,?),1.54(2H,m), 0.9(3H,t)+isopropanol (0.69 mole %) at 3.79 and 1.04; m/e384(M+H)⁺. Calculated for C₂₂ H₂₉ N₃ O₃. 0.7C₃ H₇ O: C, 68.0; H, 8.2; N,9.9. Found C, 68.1; H, 8.2; N, 9.9%.

EXAMPLE 138 Ethyl 4- 2-methyl-4-4-(4-pyridyl)piperazin-1-yl!-phenoxy!butyrate

In a similar manner to Example 25, but starting from 2-methyl-4-4-(4-pyridyl)piperazin-1-yl!phenol dihydrochloride was prepared thetitle compound in 29% yield as a gum; NMR(CDCl₃ δ 8.3(2H,m),6.45-6.35(5H,m), 4.14(2H,q), 3.87(2H,t), 3.14(4H,m), 2.53(2H,t),2.21(3H,s), 2.11(2H,m), 1.24(3H,t); m/e 384(M+H)⁺.

The necessary starting material was made as follows: i) Carbonyldiimidazole (5 g) was added portionwise to a stirred suspension ofN-benzyliminodiacetic acid (3.14 g) in dry THF (50 ml) at roomtemperature under argon. After 5 minutes, the mixture was heated atgentle reflux for 15 minutes and (4-amino-2-methyl)-phenylbenzylether(3.0 g) added and the mixture stirred at reflux for 17 hours. Solventwas evaporated and the residue was stirred with ethyl acetate (100 ml)and water (150 ml) for 11/2 hours. The solid was filtered, washed withwater and dried to give (4-4-benzyl-2,6-diketopiperazin-1-yl!-2-methyl)phenylbenzylether (4.7 g);m.p. 118-126° C. (dec); NMR (CDCl₃) δ 7.1-7.32(10H,m), 6.78(3H,s),4.93(2H,s), 3.56(2H,s), 3.4(4H,s): 2.12(3H,s); m/e 373(H+H)⁺.

(ii) To a solution of the product of step i) (2.9 g) in dry THF (50 ml)was added lithium aluminium hydride (0.6 g) and the mixture heated atreflux for 11/2 hours. The mixture was allowed to cool and more (0.3 g)lithium aluminium hydride added arid reflux continued for a further 11/2hours. The mixture was cooled and water (0.9 ml) added followed bysodium hydroxide solution (1N, 3.6 ml) and the mixture refluxed for 10minutes. The solid was filtered and washed with THF. The filtrate andwashings were evaporated and the residue purified by flashchromatography on silica gel, eluting with 5% ethyl acetate indichloromethane increasing to 25% ethyl acetate. Thus was obtained2-methyl-4-{4-benzylpiperazin-1-yl}!phenylbenzyl ether as a solid (1 g);m.p. 118°-120° C.; NMR(CDCl₃) δ 7.2-7.5(10H,m), 6.82(1H,d), 6.80(1H,d),6.7(1H,m), 5.01(2H,s), 3.1(4H,m), 2.53(3H,s); m/e 373(M+H)⁺.

(iii) A suspension of the product of step ii) (1 g) in1,2-dichloroethane (25 ml) was cooled in ice-water and treated with1-chloroethylchloroformate (0.77 g). The mixture was allowed to warm toroom temperature, stirred for 30 minutes and heated at reflux for 30minutes. Methanol (20 ml) was added and the mixture refluxed again for30 minutes and evaporated. The residue was triturated with ether andfiltered. The solid was washed with ether and dried to give 2-methyl-4-piperazin-1-yl!!phenylbenzylether hydrochloride (0.95 g); m.p.195°-198° C.; NMR(d₆ DMSO) δ 9.44(2H,bs), 7.3-7.5(6H,m), 6.98(2H,m),5.08(?,s), 4.98(4H,bs), 3.38(4H,d), 2.2(3H,s); m/e 281(M+H)⁺.

(iv) A mixture of the product of step iii) (0.95 g), 4-chloropyridinehydrochloride (0.46 g) and triethylamine (0.615 g) in water (10 ml) washeated at 100° C. for 3 hours. More 4-chloropyridine (0.34 g) andtriethylamine (0.3 ml) was added and reflux continued for a further 3hours. The solution was cooled and extracted with dichloromethane (2×15ml). The organic layer was evaporated and the residue was purified byflash chromatography on silica gel, eluting with 5% methanol indichloromethane, containing 0.4% concentrated ammonia, to give2-methyl-4- 4-(4-pyridyl)piperazin-1-yl!!-phenylbenzyl ether (0.26 g);as a solid; NMR(d₆ -DMSO) δ 8.19(2H,d), 7.25-7.5(5H,m), 6.88(4H,m),6.74(1H,m), 5.03(2H,s), 3.44(4H,bt), 3.1(4H,bt), 2.18(3H,s); m/e360(M+H)⁺.

(v) A solution of the product of step (iv) (0.52 g) in ethanol (20 ml)containing 2N hydrochloric acid (2 ml) was stirred with 10%palladium/carbon (0.16 g) under an atmosphere of hydrogen until hydrogenuptake was complete. The mixture was filtered and the filtrateevaporated. The residue was triturated with hot ethyl acetate andfiltered to give, as a solid, 2-methyl-4-4-(4-pyridyl)-piperazin-1-yl!phenol dihydrochloride (0.55 g); NMR(d₆-DMSO) δ 8.25(2H,d), 7.24(2H,d), 7.12(2H,bd), 6.8(1H,d), 4.02(4H,m),3.46(4H,m), 2.1(3H,s); m/e 270(M+H)⁺.

EXAMPLE 139 4- 2-methyl-4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!-butyricacid

In a similar manner to Example 26, but starting from the product ofExample 138, the title compound was obtained in 80% yield as a solid,m.p. 261°-262° C.; NMR(d₆ DMSO) δ 8.18(2H,d), 6.7-6.9(2H,m), 3.9(2H,t),3.43(4H,bt), 3.1(4H,bt), 2.39(2H,t), 2.13(3H,s), 1.72(2H,m); m/e356(M+H)⁺. Calculated for C₂₀ H₂₅ N₃ O₃ : C, 67.6; H, 7.1; N, 11.8.Found: C, 67.4; H, 6.9; N, 12.2%.

EXAMPLE 140 RS Methyl 2-t-butoxycarbonylamino-4- 4-4-(4-pyridyl)-piperazin-1-yl!phenoxy!butyrat

In a similar manner to Example 25 but starting from RS methyl4-bromo-2-t-butoxycarbonylaminobutyrate, the title compound was preparedin 65% yield as an oil; NMR(CDCl₃) δ 8.31(2H,d), 6.9(4H,m), 6.71(2H,m),5.3(1H,br), 4.5(1H,br.d), 4.01(2H,t), 3.77(3H,s), 3.5(4H,m), 3.21(4H,m),2.3(2H,m), 1.46(9H,s); also signals at 6.03, 2.97 and 2.9(DMF) and1.8(H₂ O); m/e 471 (M+H)⁺. Calculated for C₂₅ H₃₄ N₄ O₅. 0.5DMF. 0.5H₂O: C, 61.7; H, 7.5; N, 12.2. Found: C, 61.8; H, 7.2; N, 11.9%.

The necessary starting material was made as follows:

A solution of RS-methyl-N-butoxycarbonyl homoserinate (1.7 g) and carbontetrabromide (3.6 g) in dichloromethane (20 ml) was stirred at 5° C.Triphenylphosphine (3.77 g) was added portionwise over 5 minutes. After2 hours at room temperature the dark solution was evaporated and theresidue triturated with ether/hexane (1/1, 30 ml) until a solid wasobtained. The solid was filtered and the filtrate evaporated. Theresidue was purified by flash chromatography, the product being elutedwith 25% ethyl acetate/hexane to give RS methyl4-bromo-2-butyloxycarbonylaminobutyrate (0.41 g) as an oil; NMR(CDCl₃) δ5.16(1H,br), 4.45(1H,m), 3.8(3H,s), 3.45(2H,t), 2.52-2.11(2H,m),1.48(9H,s); m/e 296(M+H)⁺.

EXAMPLE 141 RS 2-t-butoxycarbonylamino-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyricacid

In a similar manner to Example 26, but starting from the compound ofExample 140, there was obtained in 58% yield, the title compound as asolid; m.p. 198.207° C.; NMR(d₆ DMSO) δ 8.2(2H,d), 6.91(6H,m),4.06(1H,m), 3.92(2H,t), 3.48(4H,t), 3.12(4H,t), 2.2-1.84(2H,m),1.37(9H,s); m/e 457(M+H)⁺. Calculated for C₂₄ H₃₂ N₄ O₅. H₂ O: C, 60.7;H, 7.2; N, 11.8. Found: C, 60.7; H, 7.2; N, 11.7%.

EXAMPLE 142 RS Methyl 2-amino-4- 4- 4-(4-pyridyl)piperazin-1-yl!-phenoxy!butyrate

The compound of Example 140 (0.96 g) in TFA (10 ml) was kept at roomtemperature for 2 hours. The solution was evaporated and the residuedissolved in water (15 ml) and the solution basified with sodiumcarbonate. The mixture was extracted three times with dichloromethane.Evaporation of the combined extracts gave the title compound (0.56 g);m.p. 125°-127° C.; NMR(d₆ DMSO) δ 8.2(2H,d), 6.92(6H,m), 4.0(2H,m),3.64(3H,s), 3.46(4H,t), 3.15(4H,t), 2.04(2H,m), 1.84(1H, m); m/e371(M+H)⁺. Calculated for C₂₀ H₂₆ N₄ O₃. 0.75 H₂ O: C, 62.5; H, 7.17; N,14.6. Found: C, 62.8; H, 6.8; N, 14.3%.

EXAMPLE 143 4- 2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!-phenoxyacetic acid, sodiumsalt

The title compound of Example 35 (0.25 g) in methanol (5 ml) was treatedwith aqueous sodium hydroxide (1N, 0.65 ml) and the mixture kept at roomtemperature for 6 hours. The solid thus formed was filtered and washedwith methanol to give the title compound (0.18 g); m.p. 317°-318° C.;NMR(d₆ DMSO) δ 8.2(2H,d), 7.89(2H,d), 6.91(2H,d), 6.83(2H,d),4.89(2H,s), 4.21(2H,s), 4.01(2H,s), 3.68(2H,m), 3.51(2H,m); m/e392(M+H)⁺ ; calculated for C₁₉ H₁₈ N₃ O₅ Na. 0.25H₂ O: C, 57.6; H, 4.6;N,10. Found: C, 57.2; H, 4.6; N, 10.4%.

EXAMPLE 144 Ethyl 4- 2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!-phenoxyacetate

A crude sample of the product of Example 36 (3.4 g) was treated with asolution, at 0° C., made by adding thionyl chloride (2.25 g) dropwise toethanol (45 ml) with stirring at below 0° C. The mixture was stirred atroom temperature for 2 hours, heated at gentle reflux for 21/2 hours,and evaporated. The residue was treated with water and adjusted to pH6with aqueous sodium bicarbonate solution. The gum which precipitated wasseparated and the aqueous solution was adjusted to pH₈ and extractedwith dichloromethane, (2×50 ml). The combined extracts were washed withbrine, dried and evaporated. The residue was purified by chromatographyusing a 10 g. Mega Bond Elut silica gel column, eluting with 5%methanol/dichloromethane/0.5% triethylamine to give the title product asa solid (0.2 g); m.p. 163°-165° C.; NMR(CDCl₃) δ 8.34(2H,m), 7.97(2H,m),6.98(2H,m), 6.63(2H,m), 4.89(2H,s), 4.7(2H,s), 4.29(2H,q), 4.1(2H,s),3.7(2H, m), 3.6(2H,m), 1.31(3H,t); m/e 398(M+H)⁺ ; calculated for C₂₁H₂₃ N₃ O₅ : C, 63.5; M, 5.83; N, 10.6. Found: C, 61.5; H, 5.9; N, 10.5%.

EXAMPLE 145 Ethyl N 4-2-(4-(4-pyridyl)piperazin-2-one-1-yl)acetyl!-phenoxyacetylglycinate

The compound of Example 36 (0.37 g) was stirred in DMF (10 ml) withhydroxybenzotriazole (0.17 g) and the mixture cooled in ice-water.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.14 g) wasadded, followed by triethylamine (0.14 ml) and the mixture stirred for30 minutes. Glycine ethyl ester hydrochloride (0.15 g) was now added,followed by triethylamine (0.28 ml). After ten minutes stirring in thecold, the mixture was allowed to warm to room temperature, stirred fortwo days and evaporated. Water (10 ml) was added to the residue andsodium bicarbonate added to pH₆₋₇. The mixture was evaporated and theresidue purified by chromatography on a Mega Bond Elut silica gel column(10 g), eluting with 2%-20% methanol/dichloromethane. The product wasrecrystallised from ethanol to give the title compound as a solid (36mg); m.p. 209°-211° C.; NMR(d₆ DMSO) δ 8.55(1H,t), 8.2(2H,brd),7.99(2H,m), 7.12(2H,m), 6.86(2H,d), 4.92(2H,s), 4.11(2H,q), 4.02(2H,s),3.9(2H,d), 3.2(2H, m), 3.52(2H,m), 1.2(3H,t); m/e 455(M+H); calculatedfor C₂₃ H₂₆ N₄ O₆ : C, 60.8; H, 5.77; N, 12.3. Found: C, 60.6; H, 5.7;N, 12.5%.

EXAMPLE 146 Ethyl 4- 2-nitro-4-4-(4-pyridyl)piperazin-1-yl!-phenoxy!butyrate

Sulphuric acid (98%, 2.5 ml) was added slowly to the compound of Example25 (1 g) with stirring at room temperature. The solution was cooled tobelow 5° C. and a mixture of nitric acid (0.18 ml) and sulphuric acid(0.18 ml) was added dropwise. The solution was stirred at below 10° C.for 11/2 hours, poured onto ice and basified with ammonia solution topH10. The mixture was extracted with ethyl acetate (2×50 ml) and theextract washed with water, dried (MgSO₄) and evaporated. The residue waspurified by flash chromatography on silica gel, the product being elutedwith 5% -10% methanol/dichloromethane to give the title product as anoil (0.18 g); NMR(CDCl₃) δ 8.32(2H,d), 7.41(1H,d), 7.14(1H,m),7.04(1H,d), 6.77(2H,m), 4.17-4.14(4H,m), 3.51-3.28(8H,m), 2.57(2H,t),2.14(2H, m), 1.28(3H,t), plus H₂ O (1.87); m/e 415(M+H)⁺ ; calculatedfor C₂₁ H₂₆ N₄ O₅. 0.25H₂ O: C, 60.1; H,6.3; N, 13.1. Found: C, 60.2; H,6.3; N 13.2%.

EXAMPLE 147 RS Methyl 2-n-butanesulphonylamino-4- 4-4-(4-pyridyl)-piperazin-1-yl!phenoxy!butyrate

n-Butanesulphonylchloride (0.233 g) was added to a stirred solution ofthe compound of Example 142 (0.5 g) and triethylamine (0.15 g) indichloromethane (15 ml) at room temperature. The solution was kept for 2days and subjected to flash column chromatography on silica gel. Theproduct was eluted with methanol/dichloromethane/0.88SG ammonia(7/93/0.7) v:v:v to give, after trituration with ether, the titlecompound in 58% yield as a solid; m.p. 124°-125° C.; NMR(CDCl₃) δ8.3(2H,d), 6.88(4H,q), 6.72(2H,m), 5.18(1H,br.d), 4.16(1H,br,q),4.08(2H,t), 3.8(3H,s), 3.47(4H,m), 3.18(4H,m), 2.98(2H,m), 2.28(2H,m),1.73(2H,m), 1.45-1.27(2H,m), 0.9(3H,t); m/e491(M+H)⁺ ; calculated forC₂₄ H₃₄ N₄ O₅ S: C, 58.8; H, 7.0; N, 11.4. Found: C, 58.4; H, 7.0; N,11.1%.

EXAMPLE 148 RS 2-n-butanesulphonylamino-4- 4- ₄-(4-pyridyl)-piperazin-1-yl!phenoxy!butyric acid

In a similar manner to Example 26, but starting from the compound ofExample 147, was prepared the title compound in 58% yield as a solid;m.p 251°-252° C.; NMR(d₆ DMSO) δ 8.18(2H,d), 7.3(1H,vbr), 6.9(6H,m),3.97(2H,t), 3.9(1H,m), 3.45(4H,t), 3.11(4H,t), 2.9(2H,t), 2.12(1H,m),1.92(1H,m), 1.58(2H,m), 0.81(3H,t); m/e 477(M+H)⁺ ; calculated for C₂₃H₃₂ N₄ O₅ S. 0.5 H₂ O: C, 56.9; H, 6.8; N, 11.5. Found: C,57.0; H, 6.8;N, 11.3%.

EXAMPLE 149 RS 3-Benzyl-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-butyric acid

In a similar manner to Example 26, but starting from RS ethyl3-benzyl-4- 4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate, wasprepared the title compound in 65% yield as a solid; m.p. 205°-206° C.;NMR (d₆ DMSO) δ 8.2(2H,d), 7.22(5H,m), 6.9(6H,m), 3.8(2H,d), 3.45(4H,m),3.15(4H,m), 2.72(2H,m), 2.5-2.18(Me₂ SO+3H,m); m/e 432 (M+H)⁺ ;calculated for C₂₆ H₂₉ N₃ O₃. 0.25H₂ O: C, 71.6; H, 6.8; N, 9.7. Found:C, 71.9; H, 6.8; N, 9.5%.

The necessary starting material was made as follows:

(i) A solution of RS 3-benzylbutyrolactone (1.14 g) in ethanol (20 ml)was stirred at 5° C. and gassed for 4 hours with a slow stream ofhydrogen bromide. The solution was kept at 5° C. for 20 hours and water(70 ml) added followed by sodium carbonate to neutralise the acid. Themixture was extracted with ethyl acetate and the organic layer filterdthrough phase separating paper and evaporated to give ethyl4-benzyl-3-bromobutyrate as an oil; NMR(CDCl₃) δ 7.24(5H,m), 4.13(2H,q);3.45(2H,m), 2.62(2H,d), 2.44(3H,m), 1.25(3H,t); m/e 285(M+H)⁺.

(ii) In a similar manner to Example 25, but starting from the product ofstep (i) was prepared RS ethyl 3-benzyl-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate in 40% yield as an oil; NMR(CDCl₃) δ 8.34(2H,d), 7.29(5H,m), 6.9(4H,m), 6.72(2H,m), 5.13(2H,q),3.85(2H,m), 3.5(4H,m), 3.3(4H,m), 2.9-2.38(5H,m), 1.26(3H,t); m/e460(M+H)⁺.

EXAMPLE 150 RS 3-phenyl-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-butyric acid

In a similar manner to Example 26, but starting from RS methyl3-phenyl-4- 4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate, wasprepared the title compound in 39% yield as a solid; m.p. 120°-125° C.;NMR(d₆ DMSO) δ 8.18(2H,d), 7.32(5H,m), 7.25(2H,d), 6.87(6H,m),4.04(2H,q), 3.45(5H,m), 3.11(4H,t), 2.71(2H,m); m/e 418(M+H)⁺ ;calculated for C₂₅ H₂₇ N₃ O₃. 0.25H₂ O: C, 7.1; H,6.5; N,9.9. Found: C,7.2; H, 6.5; N,9.8%.

The necessary starting material was made as follows:

In a similar manner to Example 133 step (ii), but starting from RS ethyl4-hydroxy-3-phenylbutyrate was made RS methyl-3-phenyl-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate in 10% yield as an oil;NMR(d₆ DMSO+CD₃ COOD) δ 8.23(2H,d), 7.3(5H,m), 7.17(2H,d), 6.95(2H,d),6.83(2H,d), 4.06(2H,m), 3.77(4H,t), 3.55(3H,s), 3.51(1H,m), 3.17(4H,t),2.83(2H,m); m/e 432(M+H)⁺.

EXAMPLE 151 3- 4-4-(4-pyridyl)piperazin-1-yl!!-N-benzylbenzamidopropionic acid

In a similar manner to Example 31, but starting from methyl 3- 4-4-(4-pyridyl)piperazin-1-yl!!-N-benzylbenzamido propionate was preparedthe title compound in 72% yield as a solid; NMR (d₆ DMSO) δ2.5-2.6(2H,m), 3.4-3.55 (6H,m), 3.75-3.85 (4H,m), 4.65 (2H,s), 6.95 (2H,d),7.15 (2H,d), 7.2-7.45 (7H,m), 8.25 (2H,d); m/e 445 (M+H)⁺ ; calculatedfor C₂₆ H₂₈ N₄ O₃.0.5H₂ O: C, 68.8; H, 6.3; N, 12.3. Found: C, 69.2; H,5.8; N, 12.4%.

The necessary starting material was prepared as follows:

(i) In a similar manner to Example 30, but using N-benzyl β-alaninemethyl ester, was prepared methyl 3- 4-4-(4-pyridyl)-piperazin-1-yl!!-N-benzylbenzamido propionate in 34% yieldas a solid;

NMR (CDCl₃) δ 2.0-2.1 (2H,m), 2.6-2.7 (2H,t), 3.35-3.4 (4H,m), 3.45-3.55(4H,m), 3.65 (3H,s), 4.65 (2H,s), 6.7 (2H,d), 6.85 (2H,d), 7.2-7.45(7H,m), 8.2-8.35 (2H,m); m/e 459 (M+H)⁺.

EXAMPLE 152 2-propyl-4- 2-4-(4-pyridyl)piperazin-2-one-1-yl!acetyl!phenoxy!acetic acid

Using the method of Example 131 but starting from methyl 2-^(n)propyl-phenoxyacetate, was prepared the title compound: NMR (d₆ DMSO) δ0.9 (3H,t), 1.55-1.7 (2H,m), 2.65 (2H,t), 3.45-3.55 (2H,m), 3.65-3.75(2H,m), 4.05 (2H,s), 4.8 (2H,s), 4.9 (2H,s), 6.85 (2H,d), 6.9 (1H,d),7.75-7.85 (2H,m), 8.2 (2H,d); m/e 412 (M+H)⁺ ; calculated for C₂₂ H₂₅ N₃O₅.0.25H₂ O: C, 63.5; H, 6.1; N, 10.1. Found: C, 63.5; H, 6.2; N, 9.9%.

The starting material was prepared as follows:

(i) In a similar manner to Example 3 step (i), but starting from 2-allylphenol, was prepared methyl 2-allyl-phenoxyacetate as an oil in 97%yield; NMR (d₆ DMSO) δ 3.45 (2H,d), 3.7 (3H,s), 4.8 (2H,s), 5.0-5.1(2H,m), 5.9-6.1 (1H,m), 6.85-6.95 (2H,m), 7.1-7.2 (2H,m); m/e 207(M+H)⁺.

(ii) The product of step (i) (5.86 g) was dissolved in methanol (100 ml)and a catalytic amount of 10% palladium on carbon was added. The mixturewas hydrogenated at atmospheric pressure for 18 hours. The mixture wasfiltered and concentrated to an oil which was purified by flash columnchromatography, eluting with ethyl acetate/hexane (10:90 v/v) to givemethyl 2-^(n) propyl-phenoxyacetate (4.82 g) as an oil; NMR (d₆ DMSO) δ1.4 (3H,t), 1.5-1.7 (2H,m), 2.6 (2H,t), 3.7 (3H,s), 4.8 (2H,s), 6.8-6.95(2H,m), 7.1-7.2 (2H,m); m/e 208 (M)⁺.

EXAMPLE 153 2-methyl-4- 2-4-(4-pyridyl)piperazin-2-one-1-yl!-acetyl!!phenoxyacetic acid

In a similar manner to Example 131, but starting from methyl2-methylphenoxyacetate , was prepared the title compound as a solid; NMR(d₆ DMSO+CD₃ COOD) δ 2.3 (3H,s), 3.6-3.7 (2H,m), 3.9-4.0 (2H,m), 4.35(2H,s), 4.8 (2H,s), 4.95 (2H,s), 6.95 (1H,d), 7.15 (2H,d), 7.8-7.9(2H,m), 8.25 (2H,d); m/e 384 (M+H)⁺ ; calculated for C₂₀ H₂₁ N₃ O₅.1H₂O: C, 59.8; H, 5.8; N, 10.0. Found: C, 59.3; H, 5.8: N, 10.1%.

EXAMPLE 154 Ethyl 4- 4-4(4-pyridyl)piperazin-2-one-1-yl!-phenoxy!butyrate

In a similar manner to that described in Example 25, but starting from4- 4-(4-pyridyl)piperazin-2-one-1-yl!phenol, the title compound wasprepared as a colourless solid (100 mg); NMR (d6 DMSO): δ 1.2 (3H,t);1.9-2.05 (2H,q); 2.45 (2H,t); 3.85 (2H,m); 3.95 (2H,m and 2H,t); 4.05(2H,q); 4.4 (2H,s); 6.9 (2H,d); 7.15 (2H,d); 7.25 (2H,d); 8.25 (2H,d);m/e 384 (M+H)⁺.

The necessary starting material was prepared as follows:

(i) To a stirred suspension of 4-(4-pyridyl) piperazin-2-one (880 mg) indimethyl formamide (20 ml) was added potassium hydride (1.0 ml of a 20%dispersion) and the mixture stirred for 0.5 hr, after which time wasadded copper (I) iodide (1.0 g). After 0.25 hr there was added4-benzyloxybromobenzene (1.2 g) and the mixture stirred at 140° C. in anargon atmosphere for 2 hr. The reaction mixture was diluted with waterand brine and extracted with dichloromethane (3×40 ml); the combinedextracts were washed with water and brine, dried (PS paper) andevaporated to give crude product as a pasty solid (2.0 g). This waspurified by flash chromatography on silica, eluting withdichloromethane/methanol/conc. ammonia (97:2.5:0.5 v/v) to give4-benzyloxy 4-(4-pyridyl)piperazin-2-one-1-yl!benzene as a colourlesssolid (1.1 g) NMR δ (d₆ DMSO): 3.7-3.9 (4H,m); 4.1 (2H,s); 5.1 (2H,s);6.85 (2H,d); 7.05 (2H,d); 7.25 (2H,d); 7.3-7.6 (5H,m); 8.2 (2H,d); m/e360 (M+H)⁺.

(ii) To a solution of the product of step (i) (1.1 g) in a mixture ofmethanol (500 ml) and tetrahydrofuran (100 ml) was added 30%palladium-on-charcoal catalyst (300 mg) and the mixture stirred in anatmosphere of hydrogen at ambient temperature and pressure until all thestarting material had been consumed. After removal of the catalyst byfiltration, the solvent was evaporated in vacuo to give 4-4-(4-pyridyl)piperazin-2-one-1-yl! phenol as a colourless solid,essentially one spot by tlc, which was used without further purificationor characterisation.

EXAMPLE 155 4- 4- 4-(4-pyridyl)piperazin-2-one-1-yl!phenoxy!butyricacid.

In a manner similar to that described in Example 26, but starting fromthe product of Example 154, the title compound was prepared as acolourless solid (95 mg); NMR (d₆ DMSO): δ 1.8.2.0 (2H,q); 2.35 (2H,t);3.7-4.0 (4H,m+2H,t); 4.3 (2H,s); 6.85 (2H,d); 7.05 (2H,d); 7.2 (2H,d);8.15 (2H,d); m/e 356 (M+H)+.

EXAMPLE 156 4- 2-Nitro-4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyricacid

In a similar manner to Example 26, but starting from the compound ofExample 146, the title compound was obtained in 68% yield as a solid;m.p. 219°-220° C.; NMR(d₆ DMSO) δ 8.2(2H,d), 7.4(1H,d), 7.27(2H,m),6.98(2H,d), 4.08(2H,t), 3.23(4H,br.t), 2.36(2H,t), 1.69(2H,m); m/e387(M+H)⁺. Calculated for C₁₉ H₂₂ N₄ O₅. H₂ O: C, 56.4; H, 5.98; N,13.9. Found: C, 56.7; H, 5.7; N, 13.9%.

EXAMPLE 157

Illustrative pharmaceutical dosage forms suitable for presenting thecompounds of the invention for therapeutic or prophylactic use includethe following, which may be obtained by conventional procedures wellknown in the art.

    ______________________________________                                        a)        Tablet I       mg/tablet                                            ______________________________________                                                  Active ingredient                                                                            1.0                                                            Lactose Ph. Eur.                                                                             93.25                                                          Croscarmellose sodium                                                                        4.0                                                            Maize starch paste                                                                           0.75                                                           (5% w/v aqueous paste)                                                        Magnesium stearate                                                                           1.0                                                  ______________________________________                                        b)        Tablet II      mg/tablet                                            ______________________________________                                                  Active ingredient                                                                            50                                                             Lactose        223.75                                                         Croscarmellose sodium                                                                        6.0                                                            Maize starch   15.0                                                           Polyvinylpyrrolidone                                                                         2.25                                                           (5% w/v aqueous paste)                                                        Magnesium stearate                                                                           3.0                                                  ______________________________________                                        c)        Tablet III     mg/tablet                                            ______________________________________                                                  Active ingredient                                                                            100                                                            Lactose        182.75                                                         Croscarmellose sodium                                                                        12.0                                                           Maize starch paste                                                                           2.25                                                           (5% w/v aqueous paste)                                                        Magnesium stearate                                                                           3.0                                                  ______________________________________                                        (d)       Capsule        mg/capsule                                           ______________________________________                                                  Active ingredient                                                                            10                                                             Lactose Ph. Eur.                                                                             488.5                                                          Magnesium stearate                                                                           1.5                                                  ______________________________________                                        (e)       Injection      mg/ml                                                ______________________________________                                                  Active ingredient                                                                            1.0                                                            (acid addition salt)                                                          Sodium chloride                                                                              9.0                                                            Purified water to 1.0 ml                                            ______________________________________                                    

EXAMPLE 158 (3R)-3-Methyl-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-butyric acid hydrochloride

Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to astirred suspension of 4- 4-(4-pyridyl)piperazin-1-yl!phenol (15.5 g) indry DMF (120 ml) and the mixture was stirred for 45 minutes at roomtemperature. tert-Butyl (3R)-3-methyl-4-(p-toluene-sulphonyloxy)butyrate(20 g) was added and the mixture was stirred at room temperature for 20hours. The mixture was evaporated and the residue was partitionedbetween dichloromethane and water. The organic layer was washed withwater, filtered through phase separating paper (Whatman IPS) andevaporated. The residue was triturated under diethyl ether. The solid soobtained was recrystallised from ethyl acetate to give tert-butyl(3R)-3-methyl-4- 4- 4-(4-pyridyl)piperazin-1-yl!phenoxy!butyrate (10.6g), m.p. 112°-113° C.; alpha!_(D) =-5.5° (conc.=1 g/100 ml of methanol;20° C.); NMR (CDCl₃) δ 8.3(2H,d), 6.89(4H,m), 6.7(2H,m), 3.79(2H,d),3.46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08.2.21(1H,m), 1.44(9H, s),1.07(3H,d).

A mixture of tert-butyl (3R)-3-methyl-4- 4-4-(4-pyridyl)-piperazin-1-yl!phenoxy!butyrate (10.53 g) and 1N aqueoushydrochloric acid (250 ml) was stirred at room temperature for 44 hours.A 1N aqueous sodium hydroxide solution (250 ml) was added and themixture was cooled to 5° C. The mixture was filtered and the filtratewas evaporated. Water (150 ml) was added and the resultant precipitatewas isolated and washed in turn with water, acetone and diethyl ether.The material so obtained was stirred with 1N aqueous hydrochloric acid(25 ml) for 16 hours. The mixture was cooled to 5° C. and filtered. Thesolid so obtained was washed in turn with water, acetone and diethylether and dried. There was thus obtained the title compound (7.9 g):m.p. 203°-205° C.; alpha!_(D) =-6.2° (conc.=1 g/100 ml of methanol; 20°C.); NMR(d₆ DMSO) δ 13.8(1H,broad), 12.1(1H,broad), 8.27(2H,d),7.28(2H,d), 6.9(4H,m), 3.8(6H,m), 3.18(4H,t), 2.45(1H, m), 2.23(1H,m),2.12(1H,m), 1.0(3H,d); m/e 356(M+H)⁺ ; calculated for C₂₀ H₂₅ N₃ O₃.HCl. H₂ O: C, 58.5; H, 6.8; N, 10.2. Found: C, 58.3; H, 6.9; N, 10.2%.

The necessary starting material was made as follows:

Sodium bis(trimethylsilyl)amide (1M in THF, 170 ml) was added dropwiseto a solution of (4S)-4-isopropyl-3-propionyloxazolidin-2-one (J. Amer.Chem. Soc., 1981, 103, 2127; 28.4 g) in dry THF (500 ml) which had beencooled to -70° C. and placed under an atmosphere of argon. The rate ofaddition was adjusted such that the temperature of the reaction mixturedid not rise above -67° C. The resultant solution was stirred at -70° C.for 30 minutes. tert-Butyl bromoacetate (42.3 g) was added dropwise andthe solution was stirred at -70° C. for 3 hours. The solution was thenallowed to warm to room temperature. The solvent was evaporated and theresidue was partitioned between diethyl ether and water. The organicphase was separated, filtered through phase separating paper (WhatmanIPD) and evaporated. The residue was triturated under hexane at -40° C.to give a solid (21.6 g). A second crop of solid (4.4 g) was obtained byevaporation of the hexane solution and purification of the residue byfiltration chromatography on silica gel (Merck 7736) starting withhexane and progressing to 1/10 ethyl acetate/hexane. The two batches ofsolid were combined and recrystallised from hexane to give (4S)-3-(2R)-3-tert-butoxycarbonyl-2-methylpropionyl!-4-isopropyloxazolidin-2-one(22.5 g), m.p. 64°-65° C.;

NMR(CDCl₃) δ 4.41(1H,m), 4.21(2H,m), 4.12(1H,m), 2.79(1H,m),2.28.2.4(2H,m), 1.41(9H,s), 1.16(3H,d), 0.9(6H,m).

Hydrogen peroxide (30%, 44 ml) and lithium hydroxide monohydrate (6.38g) were added in turn to a stirred mixture of (4S)-3-(2R)-3-tert-butoxycarbonyl-2-methylpropionyl!-4-isopropyl-oxazolidin-2-one(22.5 g), water (280 ml) and THF(800 ml) which had been cooled to 5° C.The resultant mixture was stirred at 5° C. for 3 hours. A saturatedaqueous sodium metabisulphite solution was added to destroy the excessof hydrogen peroxide and the solvent was evaporated. The residue wasextracted with dichloromethane. The aqueous solution was acidified bythe addition of an aqueous citric acid solution and extracted withdichloromethane. The extracts were combined, washed with water andfiltered through phase separating paper. The filtrate was evaporated togive 1-tert-butyl (3R)-3-methylsuccinate as an oil (12.9 g): NMR(CDCl₃)δ 2.9(1H,m), 2.64(1H,m), 2.37(1H,m), 1.4(9H,s), 1.23(3H,d).

Borane-dimethyl sulphide complex (10M, 10.3 ml) was added during 15minutes to a stirred mixture of 1-tert-butyl (3R)-3-methylsuccinate(12.9 g) and THF (200 ml) which had been cooled to -10° C. and placedunder an atmosphere of argon. The mixture was stirred at -10° C. for 30minutes. The mixture was allowed to warm to room temperature and wasstirred for 1 hour. The mixture was recooled to 5° C. and methanol (50ml) was added portionwise. The mixture was allowed to warm to roomtemperature and was stirred for 30 minutes. The mixture was evaporatedand the residue was partitioned between dichloromethane (100 ml) andwater (100 ml). The organic phase was filtered through phase separatingpaper and evaporated to give tert-butyl (3R)-4-hydroxy-3-methylbutyrateas an oil (11 g); NMR(CDCl₃) δ 3.55(2H,m), 2.1-2.4(3H,m), 1.46(9H,s),0.98(3H,d).

p-Toluenesulphonyl chloride (13.2 g) was added portionwise to a stirredmixture of tert-butyl (3R)-4-hydroxy-3-methylbutyrate (11 g),triethylamine (21 ml) and dichloromethane (120 ml) and the mixture wasstirred at room temperature for 20 hours. The mixture was washed in turnwith water and with a dilute aqueous sodium carbonate solution. Theorganic solution was filtered through phase separating paper andevaporated to give tert-butyl(3R)-3-methyl-4-(p-toluenesulphonyloxy)-butyrate as an oil (20 g):NMR(CDCl₃) δ 7.6(2H,d), 7.33(2H,d), 3.92(2H,d), 2.45(3H,s),2.18.2.47(2H,m), 2.0-2.15(1H,m), 1.42(9H,s), 0.95(3H,d).

We claim:
 1. A pharmaceutical composition comprising a compound offormula I: ##STR27## wherein: M² is --NR⁴ --D--TR⁵ -- in which T is N; Dis CH₂ CO or CH₂ CH₂ ; and R⁴ and R⁵ together represent CH₂ CH₂ ;X¹ is abond; Z¹ and Z^(1a) each independently represents hydrogen, hydroxy,halogeno, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,(1-4C)alkylthio, (2-4C)alkenyloxy, nitro, amino, (1-4C) alkylamino,(2-4C) alkanoylamino, cyano, (1-4C) alkylsulphonylamino; phenyl (1-2C)alkylsulphonylamino, p-toluenesulphonylamino, or (1-4C)alkoxycarbonyl,or has one of the meanings given for X² --A¹ ; X² is anoxy(2-4C)alkylene or oxy(5-6C)alkylene group, which group optionally maybe substituted on the alkylene by any of (2-4C) alkenyl, (2-4C) alkynyl,carboxy, (1-4C) alkoxycarbonyl, phenyl (1-4C) alkoxycarbonyl, phenyl(1-2C) alkylNHCO, phenyl (1-2C) alkyl, pyridyl, phenyl, amino or a groupof the formula NR¹² XR⁶ in which X is SO₂, CO or CO₂, R¹² is hydrogen or(1-4C)alkyl and R⁶ is (1-6C)alkyl, (6-10C)aryl or(6-10C)aryl(1-4C)alkyl; A¹ is carboxy or a metabolically labile ester oramide thereof; and R¹³ is hydrogen, (1-4C)alkyl, (1-4C)alkoxy orhalogen; or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier.
 2. A pharmaceuticalcomposition comprising a compound of formula I: ##STR28## wherein: M² is--NR⁴ --D--TR⁵ -- in which T is N; D is CH₂ CO or CH₂ CH₂ ; and R⁴ andR⁵ together represent CH₂ CH₂ ;X¹ is a bond; Z¹ and Z^(1a) eachindependently represents hydrogen, (1-4C)alkyl, (2-4C)alkenyl, or nitro;X² is an oxy(2-4C)alkylene or oxy(5-6C)alkylene group, which groupoptionally may be substituted on the alkylene by any of (2-4C)alkenyl,phenyl(1-2C)alkyl, phenyl, amino or a group of the formula NR¹² XR⁶ inwhich X is SO₂ or CO₂, R¹² is hydrogen and R⁶ is (1-6C)alkyl; A¹ iscarboxy or a metabolically labile ester or amide thereof; and R¹³ ishydrogen; or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier.
 3. A pharmaceuticalcomposition as claimed in claim 1 or 2, in which X¹ is a bond; and X² isan oxypropylene group, which group optionally may be substituted on thepropylene by (2-4C)alkenyl, phenyl(1-2C)alkyl, phenyl, amino or a groupof the formula NR¹² XR⁶ in which X is SO₂ or CO₂, R¹² is hydrogen and R⁶is (1-6C)alkyl.
 4. A pharmaceutical composition as claimed in claim 1 or2, in which X¹ is a bond; and X² is a 2-oxyethylene, 3-oxypropylene,4-oxybutylene or 5-oxypentylene group, which group optionally may besubstituted by any of (2-4C)alkenyl, phenyl(1-2C)alkyl, phenyl, amino ora group of formula NR¹² XR⁶ in which X is SO₂ or CO₂, R¹² is hydrogenand R⁶ is (1-6C)alkyl.
 5. A pharmaceutical composition as claimed inclaim 1 or 2, in which X¹ is a bond; and X² is an OCH₂ CH₂ CH₂ or OCH₂CH(CH₃)CH₂ group, the CH₃ group optionally being replaced by a vinyl,benzyl or phenyl group.
 6. A pharmaceutical composition as claimed inclaim 1 or 2, in whichM² is piperazin-1,4-diyl, or2-oxo-piperazin-1,4-diyl; X¹ is a bond; Z¹ and Z^(1a), together with thephenylene to which they are attached, form 1,4-phenylene,2-allyl-1,4-phenylene, 2-propyl-1,4-phenylene, 2-nitro-1,4-phenylene or2-methyl-1,4-phenylene; X² is an OCH₂ CH₂ CH₂ or OCH₂ CH(CH₃)CH₂ group,the CH₃ group optionally being replaced by a vinyl, benzyl or phenylgroup; A¹ is carboxy or a metabolically labile ester or amide thereof;and R¹³ is hydrogen; or a pharmaceutically acceptable salt thereof.
 7. Apharmaceutical composition comprising a compound selected from:4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid; 3-methyl-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid; 4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!-3-vinylbutyric acid; 4- 2-allyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid; 4- 2-n-propyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid; 4- 2-methyl-4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid; and metabolicallylabile esters and amides thereof, and pharmaceutically acceptable saltsthereof, together with a pharmaceutically acceptable diluent or carrier.8. A pharmaceutical composition comprising the compound 3-methyl-4- 4-4-(4-pyridyl)piperazin-1-yl!phenoxy!butyric acid, or a metabolicallylabile ester or amide thereof, or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable diluent or carrier.